Renal Health Through Medicine–Food Homology: A Comprehensive Review of Botanical Micronutrients and Their Mechanisms

Abstract

Background: As an ancient concept and practice, “food as medicine” or “medicine–food homology” is receiving more and more attention these days. It is a tradition in many regions to intake medicinal herbal food for potential health benefits to various organs and systems including the kidney. Kidney diseases usually lack targeted therapy and face irreversible loss of function, leading to dialysis dependence. As the most important organ for endogenous metabolite and exogenous nutrient excretion, the status of the kidney could be closely related to daily diet. Therefore, medicinal herbal food rich in antioxidative, anti-inflammation micronutrients are ideal supplements for kidney protection. Recent studies have also discovered its impact on the “gut–kidney” axis. Methods: Here, we review and highlight the kidney-protective effects of botanicals with medicine–food homology including the most frequently used Astragalus membranaceus and Angelica sinensis (Oliv.) Diels, concerning their micronutrients and mechanism, offering a basis and perspective for utilizing and exploring the key substances in medicinal herbal food to protect the kidney. Results: The index for medicine–food homology in China contains mostly botanicals while many of them are also consumed by people in other regions. Micronutrients including flavonoids, polysaccharides and others present powerful activities towards renal diseases. Conclusions: Botanicals with medicine–food homology are widely speeded over multiple regions and incorporating these natural compounds into dietary habits or as supplements shows promising future for renal health.

1. Introduction

The kidneys are indispensable for human physiological functions, including the excretion of drugs and nutrients. The kidneys maintain the balance of water, electrolytes, and endogenous metabolites throughout the body through the processes of glomerular filtration, tubular reabsorption, and tubular secretion. Additionally, they serve as the predominant organ responsible for the excretion of exogenous substances, including drugs and food nutrients [1]. However, this feature also renders the kidneys highly susceptible to acute or chronic injuries caused by these exogenous substances [2]. For example, drug-induced nephrotoxicity (DIN) accounts for up to 60% of cases of acute kidney injury (AKI) and the correlation increases in elder patients [1,3]. Dietary-resourced substances could also lead to abnormal renal status, for instance, oxalate and oxalate precursors as key determinants of urinary oxalate excretion and stone disease. In addition to certain substances that induce injury, the kidney is also affected by metabolic disorders (e.g., diabetic kidney disease) and immune abnormalities (e.g., membranous glomerulonephritis and immunoglobulin A nephropathy). The underlying molecular mechanism of kidney disorders is a complex phenomenon involving oxidative stress, inflammation, fibrosis, and mitochondrial dysfunction. Recently, the vital role of the “gut–kidney” axis, which is closely related to daily diet, has been identified and investigated [4]. However, contemporary renal disease therapy is predominantly supportive, comprising diuretics, renin–angiotensin–aldosterone system inhibitors, and immunosuppressants with a paucity of targeted pharmaceutical agents [2]. Meanwhile, these treatments could hardly reverse the continuous decline in renal function and the formation of end-stage renal disease (ESRD) [5]. Compared to drug treatment, certain daily diet patterns may also have an impact on renal function [6,7]. Natural food plants are extremely wealthy in nutrients and biological active compounds worth exploring and utilizing. Therefore, there is a promising future to explore botanicals with medicine–food homology to alleviate or prevent kidney disease.

In fact, the concept of food as medicine, or “Yao Shi Tong Yuan” in Chinese, is a fundamental tenet of Traditional Chinese Medicine (TCM). It underscores the dual function of specific foods in offering both nutritional and therapeutic advantages. The use of herbal food for medical purposes has a long and illustrious history in numerous other regions, including Japan, Korea, South America, and Europe. Despite the complexity of its ingredients, preparation methods, and active components, medicinal herbal food has been shown to have significant effects on a number of disorders, including diabetes mellitus, allergic diseases, pancreatitis, depression, and renal disease [8,9,10,11]. In the context of renal disease, a considerable number of botanical foods have been observed to exert a protective effect, as evidenced by a reduction in serum creatinine, blood urea nitrogen, histopathological injury, and fibrosis degree [12,13,14]. Early in 2002 [15], the National Health Commission (NHC) of the People‘s Republic of China had published the list of natural medical food including mostly different kinds of herbal ones. Being up to date, the list has expanded to 102 kinds of natural food including Astragalus membranaceus, Codonopsis tangshen Oliv., and Poria cocos (Schw.) Wolf. These herbal foods are frequently consumed by Chinese people either for their flavors or their potential health benefits. Many of them had also demonstrated renal-protective effects through anti-inflammation [16], antioxidation [17,18], and regulating mitochondria [19] and gut microbiota [20] with various micronutrients in them. The Food and Drug Administration (FDA) of the US have also established guidelines for the safety and efficacy of dietary supplements for medical use [21]. The 2020–2030 strategic plan for nutrition research by National Institutes of Health (NIH) had even placed “food as medicine” as one of the strategic goals [22], indicating the potential of medicine–food homology.

Here, we reviewed the frequently used medicinal herbal food in China, the US, and Europe, and summarized the potential renal-protective effects and mechanism of these medicinal herbal foods as shown in Figure 1, providing a better basis for utilizing and exploring the key substances in botanicals with medicine–food homology.

2. Botanical Ingredients with Medicine–Food Homology in China, the US, and Europe

The use of botanical ingredients for dietary supplements or even for food is a widespread tradition around the world. In addition to China, the popularity of botanical dietary supplements is also evident in various European countries. Dietary supplements represent 15–20% of the total botanical market [23]. However, the complex compounds present in botanical ingredients also pose a potential risk. One of the most illustrative examples of a botanical-induced health risk is the aristolochic acid nephropathy (AAN) incident that occurred in the early 1990s [24]. The ingestion of aristolochic acids present in certain herbs had resulted in the development of AAN in numerous patients, leading to chronic renal failure and ESRD in Belgium, China, and Korea [24,25,26]. Considering the widespread and covert use of herbs, some researchers estimated that the AAN was still underestimated and called for a stronger and systematic supervision system of herbal medicine or ingredients [25]. To ensure the safety and efficiency of botanical ingredients and supplements, many regulations and standards have been published to restrict the addition of botanical ingredients in dietary supplements. In 2002, the NHC of China had published the first index of ingredients that could be both food and medication [15]. The initial version contained 92 unique edible parts including mostly botanical ingredients. Many of them have long been thought to have kidney-protective effects like Astragalus membranaceus and Lycium barbarum L. [16,27,28]. In recent years, there has been a growing interest in botanical dietary supplements, leading the NHC to edit the index in 2019 [29] and 2023 [30]. This resulted in the addition of 15 new botanical ingredients. In 2021, the NHC had also published related regulations for this index including the criteria for botanical ingredients as both food and medication [31]. The fundamental criteria consist of the following requirements: (i) have been traditionally consumed as food; (ii) have been listed in the Pharmacopoeia of the PRC; (iii) no food safety problems have been found in the safety assessment; (iv) comply with relevant laws and regulations on the protection of Chinese herbal medicines, wild animals, plants, and ecological resources. For the first rule, it also requires evidence for the ingredients to have been consumed as food for more than 30 years. Concurrently, all of these ingredients are also included in the Pharmacopoeia of the People’s Republic of China, which demonstrates their efficacy as medicinal agents. In addition to botanicals that are regarded as both food and medicine, the NHC had also delineated a list of medicinal herbs that may be included in dietary supplements (Table S1) [15]. With regard to the European countries, the regulation of botanical ingredients is also divided into two distinct categories: medicine and food supplements. The European Medicines Agency (EMA) bears the responsibility of assessing the safety and efficacy of herbal preparations when utilized as medicines, while the European Food Safety Authority (EFSA) is tasked with the oversight of herbal preparations employed as food supplements. The evaluation of botanicals used in food products was initiated in 2004, when the EFSA mandated its Scientific Committee to develop a science-based toolkit for the safety assessment of botanicals and botanical preparations [32]. Subsequently, in 2009, the EFSA published the inaugural edition of the Compendium of Botanicals, which provided information regarding the safety risks associated with botanical ingredients in dietary supplements [32]. In the United States, the Dietary Supplement Health and Education Act (DSHEA) of 1994 initially delineated the status of herbs in dietary supplements, alongside that of vitamins, minerals, amino acids, and other substances [33]. While there is no comprehensive list of ingredients used in dietary supplements by the FDA, the NIH has established a Dietary Supplement Label Database (DSLD) [34] that includes as many of these supplements as possible.

Table 1. The full list of botanicals in the China index for medicine–food homology.

Latin Name	English Common Name	EMA Herbal Medicine	EFSA Compendium	NIH DSLD
Eugenia caryophyllata Thunb.	Clove	√	√	√
Illicium verum Hook. f.	Star anise		√	√
Canavalia gladiata (Jacq.) DC.	Sword bean			√
Foeniculum vulgare Mill.	Fennel	√	√	√
Cirsium setosum (Willd.) MB.	Thistle
Dioscorea opposita Thunb.	Chinese yam			√
Crataegus pinnatifida Bge. var. major N.E.Br./Crataegus pinnatifida Bge.	Hawthorn	√	√	√
Portulaca oleracea L.	Purslane		√	√
Prunus mume (Sieb.) Sieb. et Zucc.	Japanese apricot		√	√
Chaenomeles speciosa (Sweet) Nakai	Flowering quince		√
Cannabis sativa L.	Hemp	√		√
Citrus aurantium L. var. amara Engl.	Bitter orange
Polygonatum odoratum (Mill.) Druce	Solomon’s seal		√
Glycyrrhiza uralensis Fisch./Glycyrrhiza inflata Bat./Glycyrrhiza glabra L.	Licorice	√	√	√
Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f./Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. var. formosana (Boiss.) Shan et Yuan	Chinese angelica		√
Ginkgo biloba L.	Ginkgo	√	√	√
Dolichos lablab L.	Hyacinth bean		√	√
Dimocarpus longan Lour.	Longan		√	√
Cassia obtusifolia L./Cassia tora L.	Sicklepod		√
Lilium lancifolium Thunb./Lilium pumilum DC.	Tiger lily		√	√
Myristica fragrans Houtt.	Nutmeg		√	√
Cinnamomum cassia Presl	Cassia	√	√	√
Phyllanthus emblica L.	Amla		√
Citrus medica L. var. sarcodactylis Swingle	Fingered citron
Prunus armeniaca L. var. ansu Maxim/Prunus sibirica L./Prunus mandshurica (Maxim) Koehne/Prunus armeniaca L.	Chinese apricot		√	√
Hippophae rhamnoides L.	Sea buckthorn
Euryale ferox Salisb.	Euryale ferox		√
Zanthoxylum schinifolium Sieb. et Zucc./Zanthoxylum bungeanum Maxim.	Sichuan pepper			√
Vigna umbeuata Ohwi et Ohashi/Vigna angularis Ohwi et Ohashi	Azuki bean
Hordeum vulgare L.	Barley		√	√
Laminaria japonica Aresch./Ecklonia kurome Okam.	Kunbu
Ziziphus jujuba Mill.	Jujube		√	√
Siraitia grosvenorii (Swingle.) C.Jeffrey ex A. M. Lu et Z. Y.Zhang	Luohanguo siraitia fruit		√
Prunus japonica Thunb.	Pruni semen		√
Lonicera japonica Thunb.	Japanese honeysuckle		√
Canarium album Raeusch.	White canarium		√
Houttuynia cordata Thunb.	Fish mint		√
Zingiber officinale Rosc.	Ginger	√	√	√
Hovenia dulcis Thunnb./Hovenia acerba Lindl./Hovenia trichocarpa Chun et Tsiang	Japanese raisin tree		√
Lycium barbarum L.	Goji berry		√	√
Gardenia jasminoides Ellis	Cape jasmine		√	√
Amomum villosum Lour./Amomum villosum Lour. var. xanthioides T. L. Wu et Senjen/Amomum longiligulare T. L. Wu	Villus amomum		√	√
Sterculia lychnophora Hance	Malva nut tree		√	√
Poria cocos (Schw.) Wolf	Poria, fu ling
Citrus medica L./Citrus wilsonii Tanaka	Citron		√	√
Mosla chinensis Maxim./Mosla chinensis Maxim. cv. Jiangxiangru	Chinese mosla		√
Prunus persica (L.) Batsch/Prunus davidiana (Carr.) Franch.	Peach		√	√
Morus alba L.	White mulberry		√	√
Citrus reticulata Blanco	Mandarin orange		√	√
Platycodon grandiflorum (Jacq.) A. DC.	Balloon flower		√	√
Alpinia oxyphylla Miq.	Sharp-leaf galangal		√	√
Nelumbo nucifera Gaertn.	Lotus leaf		√	√
Raphanus sativus L.	Radish seed		√	√
Alpinia officinarum Hance	Lesser galangal		√	√
Lophatherum gracile Brongn.	Lophatherum		√	√
Glycine max (L.) Merr.	Soybean	√	√	√
Chrysanthemum morifolium Ramat.	Chrysanthemum		√	√
Cichorium glandulosum Boiss. et Huet/Cichorium intybus L.	Chicory		√
Polygonatum kingianum Coll.et Hemsl./Polygonatum sibiricum Red./Polygonatum cyrtonema Hua	Polygonati rhizoma		√
Sinapis alba L.	White mustard		√	√
Perilla frutescens (L.) Britton	Perilla		√	√
Pueraria lobata (Willd.) Ohwi/Pueraria thomsonii Benth.	Kudzu		√	√
Sesamum indicum L.	Sesame		√	√
Piper nigrum L.	Black pepper		√	√
Sophora japonica L.	Sophora		√	√
Taraxacum mongolicum Hand. Mazz./Taraxacum borealisinense Kitam.	Dandelion	√	√	√
Torreya grandis Fort.	Torreya		√	√
Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex H. F. Chou	Chinese date
Imperata cylindrical Beauv. var. major (nees) C. E. Hubb.	Cogongrass
Phragmites communis Trin.	Reed		√	√
Mentha haplocalyx Briq.	Chinese mint	√	√	√
Coix lacryma-jobi L. var. mayuen (Roman.) Stapf	Job’s tears		√	√
Allium macrostemon Bge./Allium chinense G. Don	Chinese onion		√
Rubus chingii Hu	Chinese raspberry	√	√	√
Pogostemon cablin (Blanco) Benth./Agastache rugosus (Fisch. et Mey.) O. Ktze.	Patchouli		√	√
Angelica sinensis (Oliv.) Diels	Angelica root	√	√	√
Kaempferia galanga L.	Aromatic ginger		√	√
Crocus sativus L.	Saffron		√	√
Amomum tsao-ko Crevost & Lemarié	Cardamom		√	√
Curcuma longa L.	Turmeric	√	√	√
Piper longum L.	Long pepper		√	√
Codonopsis pilosula (Franch.) Nannf./Codonopsis pilosula Nannf. var. modesta (Nannf.) L. T. Shen/Codonopsis tangshen Oliv.	Dangshen		√	√
Cistanche deserticola Y. C. Ma	Desert cistanche		√	√
Dendrobium officinale Kimura et Migo	Chinese orchid		√	√
Panax quinquefolius L.	American ginseng		√	√
Astragalus membranaceus (Fisch.) Bge.	Mongolian milkvetch (huangqi)		√	√
Ganoderma lucidum (Leyss. ex Fr.) Karst./Ganoderma sinense Zhao, Xu et Zhang	Ganoderma
Cornus officinalis Sieb. et Zucc.	Japanese cornel dogwood		√
Gastrodia elata Bl.	Gastrodia		√	√
Eucommia ulmoides Oliv.	Hardy rubber tree		√	√

EMA: European Medicines Agency; EFSA: European Food Safety Authority; NIH: National Institutes of Health; DSLD: Dietary Supplement Label Database; √: Indicating this botanical also appears in the index or database of ingredients; var.: Variety; f.: Form; cv.: Cultivar.

shows a full list of botanicals in the China index for botanicals with medicine–food homology. It contains a total of 91 botanicals, the majority of which are also included in dietary supplements in the United States and the European Union, as indicated by the EFSA Compendium of Botanicals and the DSLD. However, only a limited number of the listed botanicals are regarded as herbal medicines in accordance with the EMA standard. This is a markedly different situation from that in China, where all the botanicals in Table 1 are also included in the country’s Pharmacopoeia. Additionally, botanicals such as clove, ginkgo, and ginger are present in all four lists or databases, which suggests their widespread popularity and efficacy as both food and medicine.

3. Nutrients from These Botanical Food Ingredients with Kidney-Protective Effects

3.1. Flavonoids

Flavonoids are polyphenolic compounds that are widely distributed in a variety of botanical foods. The basic chemistry structure of flavonoids consists of two benzene rings with a phenolic hydroxyl group and a heterocyclic ring forming a C6-C3-C6 basic carbon framework [35]. The structure can be further categorized into flavanones, flavones, flavonols, flavanols, dihydroflavonols, and anthocyanins based on different functional groups and their positions [36]. It is one of the most bioactive and common compounds in food resources, especially botanicals. As demonstrated in

Table 2. Nutrients from these botanical food ingredients with kidney-protective effects.

Botanical Resources	Compounds	Models	Effects	Ref.
Flavonoids
Allium macrostemon Bge., Crocus sativus L., Plantago asiatica L. S	Quercetin	DN rats, ochratoxin A-induced AKI mice	↓ PI3K/AKT signaling ↑ Nrf2/HO-1, fatty acid oxidation	[37,38,39,74,75]
Glycine max (L.) Merr., Lonicera japonica Thunb., Ginkgo biloba L., Lycium barbarum L., Plantago asiatica L. S	Kaempferol	CLP-induced AKI mice, DN mice, DOX-induced AKI mice	↓ ICAM-1, VCAM-1, MCP-1, caspase-3, Bax, MAPK signaling, TGF-β1, and α-SMA ↑ Bcl-2, SOD, and GSH	[40,76,77,78]
Myricaceae, Polygonaceae, Primulaceae, Pinaceae, and Anacardiaceae	Myricetin	DN mice, EG-induced AKI mice	↓ IL-1β, TNF-α, ROCK1/ERK/P38 signaling, and NF-κB signaling ↑ Nrf2, CAT, and SOD	[41,42,79]
Ginkgo biloba L., Hippophae rhamnoides L., Citrus reticulata Blanco, Citrus aurantium L., and Citrus medica L.	Isorhamnetin	LPS-induced AKI mice	↓ IL-1β, IL-6, and TNF-α and M1 macrophage ↑ M2 macrophage	[43,44]
Epimedium brevicornu Maxim. S	Icariin	Adenine/UUO-induced CKD rats, DOX-induced AKI mice	↓ TGF-β, α-SMA, and E-cadherin ↑ Nrf2/HO-1, SOD, CAT	[47,48,80,81,82]
Plantago asiatica L. S	Apigenin	DOX/EG/oxonate-induced AKI mice, UAN mice	↓ Oxidative and nitrosative stress, IL-6, TNF-α, NLRP3, caspase-1, IL-1β, TGF-β, Wnt/β-catenin signaling	[49,50,83,84,85,86,87]
Citrus reticulata Blanco, Citrus aurantium L., Citrus medica L.	Nobiletin	IRI-induced AKI mice	↑ PI3K/AKT signaling	[55]
Crataegus pinnatifida Bge.	Vitexin	UUO-induced CKD mice, oxalate-induced AKI mice	↓ NLRP3, caspase-1, and IL-1β ↑ Nrf2/HO-1, SOD, GSH	[56,57]
Citrus reticulata Blanco, Citrus aurantium L., Citrus medica L.	Hesperidin, hesperetin	LPS/Zn-induced AKI mice, DDP-induced HK-2 cells	↓ p53, caspase-3 ↑ Nrf2/HO-1, SOD, GSH, and CAT Regulating gut microbiota	[58,59,60,61]
Plantago asiatica L. S	Luteolin	Cd/HgCl2/K2Cr2O7-induced AKI mice, LN mice	↓ HIF-1α, α-SMA, collagen I, and fibronectin ↑ Nrf2/HO-1, GSH, SOD, CAT, and AMPK/mTOR autophagy	[88,89,90,91,92]
Pueraria lobata (Willd.) Ohwi	Puerarin	DN mice, UUO-induced CKD mice	↑ Nrf2, cAMP/PKA/CREB ↓ TLR4/MyD8, and M1 macrophage	[72,93,94,95]
Polysaccharides
Astragalus membranaceus (Fisch.) Bge.	/	DDP-induced AKI mice	↓ ROS generation and mitochondrial vacuolation	[19]
	/	LPS-induced AKI mice	↓ Caspase-3/9 and Bax ↑ Bcl-2	[96]
	/	LPS-induced AKI mice	Regulating gut microbiota ↑ SCFAs	[97]
Bletilla striataS	Mw: 260 kDa	Ang II-induced HMCs	↓ ROS generation and NOX4	[18]
	/	TGF-β-induced HMCs	↓ TGF-β, and α-SMA	[98]
Ganoderma lucidum (Leyss. ex Fr.) Karst.	Mw: 72.9 kDa; Ara:Gal:Rha:Glc = 0.08:0.21:0.24:0.47	DN mice	↓ Collagen-1, fibronectin, α-SMA, TGF- β, and MAPK/NF-κB signaling	[99]
	/	IRI-induced AKI mice	↓ p53, caspase-3, Bax, cytochrome c, and ER stress ↑ Bcl-2	[100]
Lycium barbarum L.	Ara:Gal:Glc:GalA:Man:Rha = 12.25: 8.66: 7.66: 2.86: 1.70: 1.00	DN mice	↓ TNF-α, IL-1β, IL-6, and NF-κB signaling	[16]
	/	Lead-induced AKI mice	↓ Bax and caspase-3 ↑ Bcl-2	[101]
Laminaria japonica Aresch./Ecklonia kurome Okam.	Mw: 7 kDa	IRI-induced AKI mice	↓ p53, Bax, MMP, and cytochrome c ↑ Bcl-2	[102]
	Mw: 1960 kDa	DOX-induced AKI mice	↓ TNF-α, IL-1β, MCP-1, and podocyte injury	[103]
	Mw: 8.84 kDa; Fuc:Gal:Man:Glc:Rha:Xyl = 1:0.057:0.041:0.008:0.029:0.019	DN mice	↓ collagen-1, fibronectin, and α-SMA	[104]
	Mw: 7 kDa	DN mice	↓ α-SMA, fibronectin, and TGF-β/Smad ↑ E-cadherin	[105]
	/	DOX-induced CKD mice	↓ α-SMA, fibronectin, and TGF-β/Smad	[106]
	Mw: 7.774 kDa	AGE-induced HRMCs	↓ Fibronectin	[107]
	Mw: 8.84 kDa	TGF-β1- or FGF-2-induced HK-2 cells	↓ α-SMA, MMP9, and EMT	[108]
Polygonatum kingianum Coll.et Hemsl./Polygonatum sibiricum Red./Polygonatum cyrtonema Hua	Mw: 141 kDa; Gal:GalA:Ara:Glc = 57.67:26.82:4.59:4.54	Uranium-induced HK-2 cells	↓ ROS ↑ GSK-3β/Fyn/Nrf2	[17]
Panax ginseng C. A. Mey. S	Glc:Gal:Ara:GalA:Rha:Man = 76.7:6.5:5.1:9.2:1.4:1.1	DDP-induced AKI mice	↓ p53, caspase-3, caspase-6, and ER stress by PERK/eIF2α/ATF4 signaling	[109]
Paeonia × suffruticosaS	Mw: 164 kDa; D-Glc:L-Ara = 3.31:2.25;	DN rats	↓ TGF-β, ICAM-1, and VCAM-1	[110]
	Mw: 164 kDa; Ara = 3.31:2.25	DN rats	Regulating gut microbiota ↑ SCFAs	[111]
Plantago asiaticaS	/	Adenine-induced rats, UAN	↓ IL-6, TNF-α, NLRP3, and caspase-1	[112]
Dendrobium officinale Kimura et Migo	/	HG-induced HK-2 cells, db/db mice	↓ TGF-β, and α-SMA ↑ SIRT1	[113]
Salvia miltiorrhiza Bunge S	/	Florfenicol-induced AKI broilers	↓ p53, caspase-3 ↑ Nrf2/HO-1	[114]
Phyllostachys nigraS	Mw: 34 kDa	DN mice	Regulating gut microbiota ↑ Lactobacillales	[20]
Terpenoids
Rehmannia glutinosaS, Plantago asiaticaS, Scrophularia ningpoensisS, and Crocus sativus L.	Catalpol	DN mice, DOX/Ang II/Fru/DDP-induced AKI mice, adenine-induced CKD mice	↓ TRPC6, NF-κB, TGF-β1/Smad, TLR4/MyD88 signaling, RAGE/RhoA/ROCK signaling ↑ AMPK signaling	[115,116,117,118,119,120,121]
Cornus officinalis Sieb. et Zucc.	Loganin	DN mice, IRI/DOX/CLP-induced AKI mice	↓ NLRP3, AGE/RAGE signaling ↑ Nrf2/HO-1	[122,123,124,125]
Gardenia jasminoides Ellis, Eucommia ulmoides Oliv., Rehmannia glutinosa S, and Scrophularia ningpoensis S	Geniposide	DN mice, CLP-induced AKI mice, H2O2-induced HK-2 cells	↓ ICAM-1, TNF-α, IL-1, IL-6, NF-κB, and NETs ↑ GSK3β, AMPK-PI3K/AKT, Bcl-2 Regulating gut microbiota	[126,127,128,129,130,131,132]
Cornus officinalis Sieb. et Zucc.	Morroniside	H2O2-induced podocytes	↓ NOX4	[133]
Canarium album Raeusch.	Oleuropein	DN mice, acrylamide-induced AKI mice	↓ TNF-α, IFN-γ, IL-2, IL-6, and IL-17α ↑ SOD, GSH-Px, and CAT	[134,135]
Poria cocos (Schw.) Wolf.	Poricoic acid (A, B, C, D, E, F, G, H, AM, AE, BM, DM, and derivatives)	UUO-induced CKD mice	↓ MMP-13, Wnt/β-catenin, TGF-β/Smad3/MAPK ↑ AMPK, Nrf2	[136,137,138,139,140,141,142]
Ligustrum lucidum Ait. S	Oleanic acid	UUO-induced CKD mice, DN mice	↓ NF-κB/TNF-α, TGF-β ↑ Nrf2/SIRT1/HO-1 Regulating gut microbiota	[143,144,145,146,147]
Alisma orientatle (Sam.) Juzep. S	Alisol (A, B, and derivatives)	IRI/DDP-induced AKI mice, UUO-induced CKD mice	↓ ICAM-1, MCP-1, COX-2, iNOS, IL-6, TNF-α, FXR activation, TGF-β/Smad3 ↑ SOD and GSH and HO-1	[148,149,150]
Panax ginseng C. A. Mey.	Ginsenosides	DDP-induced AKI mice, renal carcinoma, DN mice, UUO-induced CKD mice	↓ ER stress, lipid peroxidation, PPARγ, and NOX4-MAPK pathways and TGF-β	[151,152,153,154,155,156,157,158]
Ganoderma lucidum (Leyss. ex Fr.) Karst.	Ganoderic acid, ganodermanontriol, lucidenic acid	ADPKD mice, IRI-induced AKI mice, UUO-induced CKD mice	↓ Ras/MAPK, TGF-β/Smad, IL-6, COX-2, and iNOS ↓ TLR4/MyD88/NF-κB, and caspase-3	[159,160,161]
Glycyrrhiza uralensis Fisch.	Glycyrrhizinic acid, glycyrrhizic acid	DN mice, TAC/PC-induced AKI mice	↓ ROS, IL-1β, IL-6, TNF-α, CCR2 ↑ AMPK/SIRT1/PGC-1α Regulates autophagy	[162,163,164,165,166,167]
Alkaloids
Ligusticum sinense Chuanxiong S	Tetramethylpyrazine	PC/IRI-induced AKI rats, DN rats	↓ CCL2/CCR2, ROS, NLRP3, TNF-α ↑ AKT, Bcl-2	[168,169,170,171,172]
Leonurus japonicus Houtt. S	Leonurine	DDP/LPS/vancomycin-induced AKI mice, UUO-induced CKD mice	↑ Nrf2 ↓ TLR4/MyD88/NF-κB, TNF-α, IL-1β, TGF-β/Smad3	[173,174,175,176,177]
Coptis chinensis	Berberine	IRI/DOX/DDP/MTX/gentamicin-induced AKI, DN mice, and UUO-induced CKD mice, UAN mice	↓ IL-6, IL-10, TGF-β/Smad3, mitochondrial stress, and ER stress ↑ Nrf2, MDA, SOD, CAT, GSH, and Bcl-2 Regulating gut microbiota	[178,179,180,181,182,183,184,185,186,187,188,189,190]
Trigonella foenum-graecum L. S	Trigonelline	ON mice, DN mice	↓ EMT, ROS, α-SMA ↑ AMPK pathway	[191,192,193,194,195,196]
Piper longum L. S	Piperlonguminine	UUO-induced CKD mice	↓ TRPC6	[197]
Sophora japonica L.	Matrine, oxymatrine	IRI/DDP/gentamicin-induced AKI mice, UUO-induced CKD mice	↓ IL-6, IL-10, TGF-β/Smad3	[198,199,200]
Nelumbo nucifera Gaertn.	Liensinine, Isoliensinine	IRI-induced AKI rats, LPS-induced AKI mice	↓ TGF-β1/Smad3	[201,202]
Nelumbo nucifera Gaertn.	Neferine, nuciferine	UAN rats, LPS/IRI-induced AKI mice, DN mice	↓ TLR4/MyD88/NF-κB, IL-1β ↑ Bcl-2	[203,204,205,206,207,208,209,210]
Others
Curcuma longa L.	Curcumin	LN mice, patulin-induced AKI mice, CKD patients, UAN rats	↑ Nrf2/FOXO-3a, GSH ↓ PI3K/AKT/NF-κB, TGF-β, ROS Regulating gut microbiota	[211,212,213,214,215]
Rheum palmatum L.	Emodin, aloe emodin, rhein	UUO-induced CKD mice/rats, DN mice	↓ IL-1β, TGF-β, PERK-eIF2α Regulating gut microbiota	[216,217,218,219,220]
Eugenia caryophyllata Thunb.	Eugenol	IRI/patulin-induced AKI mice	↓ TGF-β ↑ Nrf2	[221,222]
Sesamum indicum L.	Sesamin	CKD mice, DDP/LPS-induced AKI mice	↑ GSH, CAT, and SOD Regulating gut microbiota	[223,224,225,226]
Ligusticum sinense Chuanxiong S	Ferulic acid	UAN mice	↓ TLR4/NF-κB Regulating gut microbiota	[227]
Lonicera japonica Thunb.	Chlorogenic acid	UAN mice	↓ IL-1β, TNF-α, IL-6 Regulating gut microbiota	[228,229,230]

^S: These botanicals are medical herbs that could be added to dietary supplements in the index of Table S1; ↑:upregulating or promoting; ↓: downregulating or inhibiting; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase 1; ICAM: Intercellular adhesion molecule; VCAM: Vascular cell adhesion molecule; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; Bax: BCL2-associated X; Bcl-2: B-cell lymphoma 2; MAPK: Mitogen-activated protein kinase; AMPK: Adenosine monophosphate-activated protein kinase; NF-κB: Nuclear factor kappa-B; mTOR: Mammalian target of rapamycin; cAMP: Cyclic adenosine monophosphate; PKA: Protein kinase A; CREB: cAMP-response element binding protein; TLR: Toll-like receptor; RAGE: Receptor for AGEs; AGEs: Advanced glycation end products; RhoA: Ras homolog family member A; Ras: Rat sarcoma; ROCK: Rho-associated coiled-coil-containing protein kinase; TGF: Transforming growth factor; iNOS: Inducible nitric oxide synthase; COX: Cyclooxygenase; CCR: Chemokine (C-C motif) receptor; CCL/MCP: Chemokine (C-C motif) ligand; PGC: Peroxisome proliferator-activated receptor-gamma coactivator; FXR: Farnesoid X receptor; α-SMA: α-Smooth muscle actin; ROS: Reactive oxygen species; GSK-3β: Glycogen synthase kinase 3 beta; SOD: Superoxide dismutase; GSH: Glutathione; CAT: Catalase; HIF: Hypoxia-inducible factor; NOX: NADPH oxidase; IL: Interleukin; TNF: Tumor necrosis factor; FOXO: Forkhead box O; ERK: Extracellular regulated protein kinase; MMP: Matrix metalloproteinase; ER: Endoplasmic reticulum; PERK: Protein kinase R-like endoplasmic reticulum kinase; eIF2α: Phosphorylation of eukaryotic initiation factor-2α; ATF4: Activating transcription factor 4; SIRT1: Silent information regulator 1; TRPC: Transient receptor potential canonical; SCFAs: Short-chain fatty acids; CKD: Chronic kidney disease; IRI: Ischemia/reperfusion injury; ADPKD: Autosomal dominant polycystic kidney disease; UUO: Unilateral ureteral obstruction; UAN: Uric acid nephropathy; CLP: Cecum ligation puncture; DOX: Doxorubicin; DDP: Cisplatin; LPS: Lipopolysaccharide; EG: Ethylene glycol; LN: Lupus nephritis; Ang II: Angiotensin II; HMCs: Human mesangial cells; HK-2 cells: Human kidney-2 cells; Fru: Fructose; TAC: Tacrolimus; PC: Post-contrast; MTX: Methotrexate; ON: Oxalate nephropathy.

, flavonoids that have been validated to have kidney-protective effects include quercetin [37,38,39], kaempferol [40], myricetin [41,42], isorhamnetin [43,44], fisetin [45,46], icariin [47,48], apigenin [49,50], baicalein [51,52], baicalin [53,54], nobiletin [55], vitexin [56,57], hesperidin [58,59], and hesperetin [60,61]. Quercetin and kaempferol appear in the majority of vegetables and fruits, which accounts for their status as the most prevalent dietary supplement ingredients. A review of the DSLD revealed that dietary supplements containing quercetin constituted 2.3% of the total products [29]. As illustrated in Table 2, citrus botanicals such as Citrus medica L. var. sarcodactylis Swingle and Citrus reticulata Blanco exhibit a notable content of flavonoids, including hesperidin, hesperetin, naringin, quercetin, and kaempferol [62,63,64]. The flavonoids present in citrus fruits have been demonstrated to possess potent antioxidant properties, making them a promising avenue of research for the development of novel therapeutic agents for the treatment of diabetes, neurodegenerative disorders, and kidney diseases such as AKI and diabetic nephropathy (DN) [65,66,67,68,69]. In addition to citrus, Glycine max (L.) Merr. (soybean) in Table 1 contains a unique kind of isoflavones called soy isoflavones, or “phytoestrogens” due to their structural similarity with 17-β-estradiol [70]. Though most of the studies of soy isoflavones fell into their endocrine regulation impacts, one recent study had discovered that the intake of soy isoflavones exhibited favorable effects on renal function and kidney morphology [71]. Puerarin, derived from Pueraria lobata (Willd.) Ohwi, is also an isoflavone. Recent studies have demonstrated its influence on the toll-like receptor (TLR) 4/MyD88 pathway and the M1 macrophage differential [72]. Later, flavonoids in Pueraria thomsonii Benth. were further found to decrease inflammation in the kidney by regulating the level of Clostridium in the gut [73]. Hesperidin from citrus botanicals could also alter gut microbiota against Zn-induced nephrotoxicity [58], indicating the potential of the gut–kidney axis.

3.2. Polysaccharides

Natural polysaccharides are a class of complex macromolecules that are formed from a variety of monosaccharide units and diverse glycosidic linkages. The monosaccharide units can be classified into several categories, including hexose, which includes glucose, galactose, and mannose; N-acetyl-hexose (HexNac), which encompasses GalNac and GluNac; pentose (e.g., xylose and arabinose); deoxyhexose (e.g., fucose); and numerous terminal modifications, such as phosphorylation, sulfation, and sialylation. Up to the present date, the identification and isolation still remain a critical challenge. However, the polysaccharides were found to be the principal compounds in some of the botanicals in Table 1 and the pharmacological effects of polysaccharides have also long been confirmed. Table 2 illustrates the representative polysaccharides from botanicals in Table 1 and Table S1, along with their impact on kidney diseases.

Laminaria japonica Aresch. is a widespread food ingredient in China with a significant amount of polysaccharides. It contains polysaccharides weighing from 5 kDa to 10⁴ kDa [231] with great potential in anti-fibrosis effects, which revealed its capacity to treat CKD [106]. In many kidney diseases including the DN model [104,105], DIN model [103,106], and IRI model [102], polysaccharides from Laminaria japonica Aresch. showed strong impact on fibrosis- and apoptosis-related molecules like TGF-β, α-SMA, and Bax/Bcl-2. Polysaccharides are also identified to be the primary compounds in Polygonatum sibiricum Red [232]. Polygonat Rhizomai polysaccharides were discovered to be protective against uranium-induced AKI with 141 kDa polysaccharides in them [17]. The polysaccharides from other traditional kidney-protective botanical food like Lycium barbarum L. [101] and Astragalus membranaceus [19,96,97] showed protective effects against DIN as well.

In consideration of the gut–kidney axis, polysaccharides derived from these botanical ingredients also play a significant role in the intricate interplay of gut–kidney crosstalk. The polysaccharides derived from Phyllostachys nigra [20], Paeonia × suffruticosa (Moutan Cortex) [111], and Astragalus membranaceus (Fisch.) Bge. [97] have been observed to possess the capacity to regulate the gut–kidney axis, thereby conferring benefit to the kidney. The mechanisms involved in remodeling the gut microbiota composition include an increase in the abundance of probiotics, such as Lactobacillales, and an upregulation of SCFAs.

3.3. Terpenoids

Terpenoids, which are derived from isoprene, encompass a diverse range of chemical compounds, including monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenes, triterpenoids, and polyterpenoids [233]. Considering the ingredients in Table 1 and Table S1, Panax ginseng C. A. Mey. (ginseng), Glycyrrhiza uralensis Fisch. (Liquorice), Alisma orientatle (Sam.) Juzep., and Ganoderma lucidum (Leyss. ex Fr.) Karst. (Ganoderma) are representative for their great amount and variety of terpenoids.

Ganoderma triterpenoids isolated from Ganoderma are some of the major chemical constituents in Ganoderma and could be further divided into C30 (ganoderic acid, ganodermanontriol, applanoxidic acids, and their derivatives), C27 (lucidenic acid, ganolactone, and their derivatives), and C24 (lucidones and their derivatives), and others according to their skeleton carbons [234]. Among the compounds identified, ganoderic acids had been proven to possess protective properties in the context of ADPKD [159], renal fibrosis [160], and IRI [161]. Licorice is another ingredient that has been demonstrated to possess renal-protective terpenoids, the most prominent of which are glycyrrhizic acid and glycyrrhetinic acid [235]. Glycyrrhizic acid possesses surprising protective effects in DN [162,163] and DIN including tacrolimus [164], contrasts [165], and triptolide [166]-induced kidney injury. Similar effects were also found in glycyrrhetinic acid in DN [162] and IRI [167]. Alisma orientatle (Sam.) Juzep. and Panax ginseng C. A. Mey. are two botanicals in Table S1, which means that they are not considered daily food but could be added to dietary supplements. However, they have been traditionally used to treat renal disorders in TCM, especially Alisma orientatle (Sam.) Juzep. Alisols and their derivatives are tetracyclic triterpene alcohols isolated from Alisma orientatle (Sam.) Juzep. and play a significant role in its pharmacological effects [236]. Recent studies had demonstrated the potential of alisols in protecting the kidney from DPP-induced injury and IRI by targeting the farnesoid X receptor and soluble epoxide hydrolase [148,149]. Additionally, alisol B 23-acetate was observed to regulate the gut microbiota, thereby improving renal function in CKD mice [150]. Ginsenosides, the representative compounds in ginseng, are a big family of triterpenoid saponins with a four-ring rigid steroid skeleton [237]. Early in 1998, a study revealed that ginsenoside Rd could protect against IRI by affecting proximal tubule cells [238]. Later, numerous studies had demonstrated that ginsenosides could alleviate AKI [151,152], renal carcinoma [153,154], DN [155,156], and renal fibrosis [157,158].

Iridoids constitute a large and distinctive class of monoterpenoids that are ubiquitous in botanical sources and have been demonstrated to exhibit notable bioactivity [239]. Iridoids are receiving increasing attention for their great pharmacological effects in the liver, kidney, and nervous disorders [240,241,242,243]. Catalpol, one of the most common iridoids, for example, showed strong antioxidation and anti-inflammation effects in DN-, CKD-, and DIN-induced AKI models [115,116,117,118,119,120,121]. Cornus officinalis Sieb. et Zucc. was found to be abundant in iridoids [244], in which loganin and morroniside were shown to be protective for the kidney [122,123,124,125,133]. The representative terpenoids including triterpenoids and iridoids from botanicals with medicine–food homology are also shown in Table 2.

3.4. Alkaloids

Isolated from natural herbs, alkaloids are a diverse group of naturally occurring organic compounds that primarily contain basic nitrogen atoms [245]. Structurally, they could be characterized by a heterocyclic ring that incorporates nitrogen, and they often possess complex and varied molecular frameworks, for example, isoquinoline, pyrrolidines, pyridines, indole, and others. Dietary botanicals also contain variable bioactive alkaloids for renal protection. Table 2 provides a list of the principal representative alkaloids with kidney-protective effects derived from the botanicals included in Table 1 and Table S1.

Tetramethylpyrazine, the characteristic alkaloid of Ligusticum sinense Chuanxiong, has been clinically utilized to inhibit platelet aggregation and reduce blood viscosity [246]. Its renal-protective effects were also validated in multiple models including DIN-induced AKI [168,169], IRI [170], and DN [171,172] with classical mechanisms targeting inflammation and oxidation markers. Leonurine from Leonurus japonicus Houtt. also showed protective effects in lipopolysaccharide-, DDP-, and vancomycin-induced AKI [173,174,175,176,177]. Besides AKI, trigonelline, the characteristic alkaloid in Trigonella foenum-graecum L. (Fenugreek) and Coffea arabica (coffee) was demonstrated to maintain a strong protective effect on oxalate nephropathy (ON) [191,192], which is closely related to diet oxalate. Nelumbo nucifera Gaertn. is well known for its abundant alkaloids, especially in its seeds. Liensinine, isoliensinine, neferine, and nuciferine are all alkaloids with kidney-protective effects isolated from Nelumbo nucifera Gaertn. Besides AKI and DN, neferine was also revealed to alleviate hyperuricemic nephropathy by targeting the inflammasome pathway [208]. Another alkaloid that has been widely studied for its protective effects on the kidneys is berberine. This isoquinoline alkaloid was initially isolated from Hydrastis canadensis and is primarily found in Coptis chinensis. Although these botanicals are not typically included in dietary regimens, berberine itself is a frequently utilized compound in dietary supplements. In DSLD, dietary supplements containing berberine reached 865 records. The renal-protective effects and mechanism of berberine have long been studied since 2011 in the DN model [247,248]. Later, the extraordinary effects of berberine were found in multiple nephropathy models including DIN-induced AKI [178,179,180,181,182], IRI-induced AKI [183,184,185], DN [186,187,188], and UUO-induced renal fibrosis [189]. The mechanisms involved in the treatment of berberine contained traditional anti-inflammation, oxidation, apoptosis, and also the regulation of gut bacteria. With the increasing interest in the gut microbiota, the interaction between the gut microbiota and berberine in the treatment of renal diseases has shown great promise. Recent studies demonstrated that berberine could improve chronic kidney disease by inhibiting the production of enterogenous toxins such as trimethylamine oxide (TMAO) and p-cresol (pCS), which are metabolites from gut microbiota [190]. Berberine could also increase the abundance of Coprococcus, Bacteroides, Akkermansia, and Prevotella to alleviate UAN [249,250,251]. A growing body of evidence suggests that the mechanisms of renoprotective effects through the gut–renal axis deserve further investigation.

Though many alkaloids possess renal-protective effects, a few studies have yielded contradictory results for the same compounds, for example, matrine from Sophora japonica L. Some studies [252,253] found that matrine could lead to kidney injury with mitochondria dysfunction and oxidation while another study demonstrated its protective effect on the DDP-induced AKI model [198]. Its derivate, oxymatrine, was also found to alleviate gentamicin-induced AKI [199], IRI [200], and renal fibrosis [254]. It again reinforces the necessity for the scientific research and regulation of the dietary utilization of botanicals with medicine–food homology.

3.5. Others

In addition to the aforementioned classes of compounds, botanicals with medicine–food homology also contain many other abundant bioactive nutrients including various kinds of polyphenols and anthraquinones, among which some showed great potential in benefiting the kidney as shown in Table 1. Simple phenylpropanoids are a kind of natural polyphenols with a three-carbon side chain linked to a phenyl ring, forming a C6-C3 skeleton. The primary structure also makes them precursors to many other natural compounds, such as flavonoids, lignans, and polyphenols [255]. Simple phenylpropanoids, including the widely distributed ferulic acid and chlorogenic acid, were both found to remodel the composition of the gut microbiota, thereby alleviating UAN [227,228,229]. Curcumin, the most bioactive and abundant polyphenol [256] in Curcuma longa L., has been extensively investigated for its potent antioxidant effects [213]. Together with its derivatives, curcumin displayed potential in treating LN [212], DIN-induced AKI [211], DN [215], and even focal segmental glomerulosclerosis (FSGS) [214]. Additionally, research has indicated that curcumin may mitigate renal impairment by modulating the microbiota in conditions such as CKD and UAN [257,258]. Sesamin, a lignan from dietary sesame, was also demonstrated to decrease uremic toxins by inhibiting the gut microbiota indole pathway [223], indicating importance of the gut–kidney axis. Anthraquinone compounds, for example, emodin and its derivatives, are the most important chemical compounds in Rheum palmatum L., which has long been used in TCM and added to dietary supplements [259]. The anthraquinone compounds in Rheum palmatum L. also possess renal-protective effects on DN, CKD, and UUO models, mainly targeting TGF-β secretion [216,217,218,219,220]. Interestingly, emodin was found to decrease uremic toxins as well by targeting gut microbiota [260]. An increasing body of evidence is emerging that demonstrates the significance of the gut–kidney axis in relation to dietary nutrients.

4. Mechanisms Involved in the Kidney-Protective Effects of Botanical Ingredients with Medicine–Food Homology

4.1. Antioxidation, Anti-Inflammation, and Anti-Fibrosis

Previous studies had focused on the inflammation/oxidation-oriented mechanisms, which are key pathological changes in kidney diseases. Oxidative stress is characterized by an initial injury in the kidney due to the activities of intra- and extracellular oxygen-derived radicals and the resultant inflammatory response [261]. When the kidney is exposed to harmful stimuli, ROS such as superoxides and hydroxyl radicals are produced in excess and interact with the molecular components and functions of a nephron such as the cell membrane, DNA methylation, histone modifications, and micro-RNAs, which are crucial mechanisms for fetal programming [262]. The production and scavenging of oxygen-derived radicals are in a dynamic balance through enzymatic (SOD, CAT, HO-1) and non-enzymatic (vitamin C, vitamin E, glutathione) antioxidant systems [263]. To deal with increased oxidative stress, several redox signaling response cascades, including Nrf2, could be activated to regulate this antioxidative gene expression [263]. Due to the existence of the oxygen shunt diffusion, the kidney is highly susceptible to oxidative stress and hypoxia [264]. Abnormalities in oxidative stress have been observed in a range of kidney diseases, including CKD, DN, and DIN-induced AKI and CKD [265,266,267,268].

The critical role of inflammation in the development of AKI, CKD, and DN was also widely confirmed in animal and clinical studies. The inflammation in the kidney is activated by various mechanisms including endothelial injury, drugs, and infection and causes glomerular, interstitial, and vascular damage [269]. The process of neutrophil infiltration is accompanied by an increase in multiple pro-inflammatory chemotaxes, adhesion factors, and chemokines, including ICAM-1, P- and E-selectin, and IL-1β, IL-6, IL-18, and TNF-α. This process is strongly correlated with fibrosis, autophagy, oxidative stress, and mitochondrial dysfunction [270]. In primary glomerular disease including acute glomerulonephritis, IgA nephropathy, and nephrotic syndrome, complement activation and immune complex deposition, which elicit strong inflammation, were also identified as key pathogenesis [271,272]. Pro-inflammatory signaling pathways include the TLR4/MyD88 signaling pathway, which is also closely related to gut microbiota due to its recognition of pathogen-associated molecular patterns [273]. The activation of TLR4 could lead to the upregulation of another key pro-inflammatory signal, the NF-κB-related pathway [273], which is also the target for most of the anti-inflammation effects in Table 2.

Fibrosis represents another pivotal pathological process following inflammation, especially chronic inflammation. With continuous inflammatory stimulation, various stromal cells in the kidney are transformed to myofibroblasts, which contribute to excessive extracellular matrix production and deposition in the renal parenchyma, eventually leading to loss of renal function [274]. The increase in the secretion of TGF-β and the fibroblast growth factor (EGF) and the secretion of type I collagen, fibronectin, chondroitin sulfate, and other components of the extracellular matrix (ECM) are also directly involved in the epithelial–mesenchymal transition (EMT) and fibrosis [275]. Recent studies had discovered that MMP also contributes to renal fibrosis [276]. There are several severe molecules and pathways involved in the complicated process of renal fibrosis, for instance, the Wnt/β-catenin and TGF-β1/Smad pathways, which are also key targets for botanicals. As the most vital target, Smad3-mediated TGF-β stimulation not only induces collagen production and the inhibition of ECM degradation, but also depresses fatty acid oxidation, leading to a profibrotic phenotype [275].

Botanicals with medicine–food homology happen to be abandoned in natural antioxidant, anti-inflammation, and anti-fibrosis compounds regulating the above pathways and inflammatory cytokines as shown in Table 2. The majority of the mechanisms underlying the protective effects are associated with these mechanisms, underscoring the significant potential and importance of incorporating daily dietary botanicals and supplements into one’s routine.

4.2. Regulating the “Gut–Kidney Axis”

In addition to the classical molecular pathological processes centered on inflammation, oxidative stress, and cellular autophagy and apoptosis, a large number of studies have recently revealed a relationship between intestinal disorders and renal disease, a link that has been increasingly emphasized and investigated under the term “gut–kidney axis” [4]. It has been suggested that the gut–renal axis can be subdivided into metabolism-dependent and immunologic pathways [277]. Metabolism-dependent pathways are mainly mediated by metabolites produced by the gut microbiota that have the ability to modulate host physiological functions. For example, alterations in the gut microbiota can lead to intestinal metabolism and dysfunction, thereby increasing uremic toxin production and renal dysfunction [190,278]. On the other hand, kidney disease also affects the composition of gut bacteria and could cause gastrointestinal dysfunction [279,280]. In addition to uremic toxins like pCS, the gut microbiota produces a large number of physiologically active substances such as SCFAs, and bile acids (BAs), which play an important role in the regulation of renal disease and function [4]. Studies have found a reduction in SCFA-producing gut bacteria including Lactobacillaceae and Prevotella species in ESRD patients compared to healthy individuals [281,282]. However, in some models of kidney disease, a high-fiber diet that promotes the growth of SCFA-producing bacteria and direct supplementation with SCFAs attenuated renal fibrosis [283]. As for the immune pathway, components of the immune system (e.g., lymphocytes, monocytes, and cytokines) play a key role in the communication between the gut and the kidney [284]. A growing number of studies have demonstrated that gut flora play a crucial role in mucosal immunity and systemic inflammation, and that changes in gut flora induce changes in inflammatory cytokine profiles in the bone marrow [285], which are further associated with the development of autoimmune nephropathy [286]. Lymphocytes could even migrate from the gut to the injured kidney via the chemokine pathway [284]. Recent studies have also found that the aberrant galactose-deficient IgA, which is key in the pathogenesis of IgA nephropathy, is associated with aberrant hydrolysis by intestinal bacteria, and is recognized in vivo through the metabolism of the intestinal bacteria exposing aberrant antigenic epitopes, which leads to the formation of immune complexes and renal deposition [286].

As attention is increasingly focused on the gut microbiota, their interaction with botanicals has been discovered and showed a promising future [287,288,289,290,291,292]. As shown in Table 2, almost all kinds of compounds have the potential in regulating gut microbiota. Panax notoginseng saponins, the bioactive components of a well-known and widely used botanical, Panax notoginseng, in Table S1, could regulate intestinal microorganisms and therefore ameliorate inflammation and fibrosis. Similarly to terpenoids, the renal protection by oleanic acid was also found to be associated with its regulation on gut microbiota [147]. Berberine had also been found to ameliorate chronic kidney disease through inhibiting the production of gut-derived uremic toxins, for example, TMAO and pCS in the gut microbiota [190]. Astragalus membranaceus, of which the anti-inflammation and fibrosis effects were confirmed, was also found to influence the gut microbiota, with Akkermansia muciniphila and Lactobacillus being the main driving bacteria [97]. More and more renal-protective effects of botanicals are found to be associated with the gut–kidney axis. Meanwhile, the gut microbiota exhibit rapid alterations in response to daily diets [293,294], indicating the potential for dietary nutrients to intervene in the gut–kidney axis.

5. Conclusions and Perspective

The concept of “food as medicine” underpins the traditional use of these botanicals, especially within the framework of TCM. This approach, which integrates dietary and medicinal uses, provides a unique and holistic perspective on disease prevention and health maintenance. The review emphasizes that many botanicals have been traditionally used for both food and therapeutic purposes, demonstrating their dual benefits. The diverse bioactive compounds found in these botanicals, such as flavonoids, polysaccharides, saponins, alkaloids, and polyphenols, demonstrate a range of protective effects on renal health. These effects are primarily mediated through antioxidation, anti-inflammation, anti-fibrosis, the modulation of the immune response, and enhancement in mitochondrial function as shown in Figure 2. The integration of these botanicals into modern therapeutic regimes could offer a complementary approach to conventional treatments for kidney diseases, which often focus on symptom management rather than disease reversal. The promising results from experimental studies suggest that incorporating these natural compounds into dietary habits or as supplements could contribute to better renal health outcomes.

A particularly notable aspect highlighted in this review is the interplay between these botanicals and the gut–kidney axis. This emerging area of research emphasizes the complex relationship between gut microbiota and renal function. Botanical compounds can influence the composition and activity of gut microbiota, which in turn affects systemic inflammation, immune responses, and metabolic processes relevant to kidney health. For instance, the modulation of gut microbiota by polysaccharides and polyphenols can lead to the production of beneficial metabolites, such as short-chain fatty acids, which have protective effects on the kidneys. Considering the close relation between daily diets and gut microbiota, the potential for dietary nutrients to intervene in the gut–kidney axis is worth deeper exploration.

In summary, botanical ingredients with medicine–food homology present a valuable resource for developing new strategies in the prevention and management of kidney diseases. By leveraging their effects on the gut–kidney axis and other pathways, these botanicals hold promise for enhancing renal health and improving patient outcomes. Continued research and clinical validation are essential to fully realize their potential in this domain.