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Renal Dysfunction, Uremic Compounds, and Other Factors

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 24968

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Special Issue Editors

Dr. Giovana S. Di Marco

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Department of Internal Medicine D, University Hospital Muenster, 48149 Münster, Germany
Interests: nephrology; endothelial dysfunction; cell biology; angiogenesis; risk factors
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Marcus Brand

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Guest Editor

Department of Internal Medicine D, University Hospital Muenster, 48149 Münster, Germany
Interests: nephrology; dialysis; cardiorenal syndrome; angiogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

When the kidneys fail, many endogenous substances accumulate in the circulation due to decreased renal clearance and increased production. These substances, including uremic toxins, inflammatory mediators, modified biomolecules, and growth factors, cause a complex local and systemic derangement in metabolism and signaling, affecting nearly all body organs and systems. This occurs not only in the setting of chronic and end-stage renal disease but also due to acute kidney injury. Therefore, identifying uremic compounds and other factors that have a biological effect on cells and tissues is necessary to understand the mechanisms linking kidney disease and other organs and build up better therapeutic strategies.

This Special Issue explores soluble mediators in renal disease (acute and chronic kidney diseases). It includes original articles and review papers reporting on aspects related to their biological effects, disease progression, involvement in inter-organ communication, and therapy. Potential topics include, but are not limited to, the search for new factors/biomarkers, the toxicity of uremic compounds, post-translational modification of proteins and peptides, molecular mechanisms of action, inflammation, the gut microbiome, organ cross-talk, and new techniques and analytical methods for the measurement and detection of soluble compounds or their (toxic) effects.

Dr. Giovana S. Di Marco
Prof. Dr. Marcus Brand
Guest Editors

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Keywords

renal dysfunction
acute kidney disease
chronic kidney disease
soluble mediators
uremic toxins
disease progression
organ cross-talk
therapy
new techniques

Published Papers (14 papers)

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13 pages, 1123 KiB

Open AccessArticle

High Plasma Angiopoietin-2 Levels Predict the Need to Initiate Dialysis within Two Years in Patients with Chronic Kidney Disease

by Anna Szymczak, Mariusz Kusztal, Tomasz Gołębiowski, Krzysztof Letachowicz, Anna Goździk, Katarzyna Kościelska-Kasprzak, Andrzej Tukiendorf and Magdalena Krajewska

Int. J. Mol. Sci. 2023, 24(12), 10036; https://doi.org/10.3390/ijms241210036 - 12 Jun 2023

Cited by 2 | Viewed by 965

Abstract

Volume status, congestion, endothelial activation, and injury all play roles in glomerular filtration rate (GFR) decline. In this study, we aimed to determine whether the plasma endothelial and overhydration markers could serve as independent predictors for dialysis initiation in patients with chronic kidney disease (CKD) 3b-5 (GFR < 45 mL/min/1.72 m²) and preserved ejection fraction. A prospective, observational study in a single academic center was conducted from March 2019 to March 2022. Plasma levels of angiopoietin (Ang)-2, Vascular Endothelial Growth Factor-C (VEGF-C), Vascular Cell Adhesion Molecule-1 (VCAM-1), Copeptin (CPP), beta-trace protein (BTP), brain natriuretic peptide (BNP), and cardiac troponin I (cTnI) were all measured. Lung ultrasound (US) B-lines, bioimpedance, and echocardiography with global longitudinal strain (GLS) were recorded. The study outcome was the initiation of chronic dialysis (renal replacement therapy) during 24 months of follow-up. A total of 105 consecutive patients with a mean eGFR of 21.3 mL/min/1.73 m were recruited and finally analyzed. A positive correlation between Ang-2 and VCAM-1 and BTP was observed. Ang-2 correlated positively with BNP, cTnI, sCr, E/e′, and the extracellular water (ECW)/intracellular water (ICW) ratio (ECW/ICW). After 24 months, a deterioration in renal function was observed in 47 patients (58%). In multivariate regression analysis, both VCAM-1 and Ang-2 showed independent influences on risk of renal replacement therapy initiation. In a Kaplan-Meier analysis, 72% of patients with Ang-2 concentrations below the median (3.15 ng/mL) survived without dialysis for two years. Such an impact was not observed for GFR, VCAM, CCP, VEGF-C, or BTP. Endothelial activation, quantified by plasma levels of Ang-2, may play a key role in GFR decline and the need for dialysis initiation in patients with CKD 3b, 4, and 5. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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17 pages, 3212 KiB

Open AccessArticle

Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model

by Lars Erichsen, Chantelle Thimm, Wasco Wruck, Daniela Kaierle, Manon Schless, Laura Huthmann, Thomas Dimski, Detlef Kindgen-Milles, Timo Brandenburger and James Adjaye

Int. J. Mol. Sci. 2023, 24(9), 8228; https://doi.org/10.3390/ijms24098228 - 4 May 2023

Cited by 1 | Viewed by 1604

Abstract

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10–15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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15 pages, 3213 KiB

Open AccessArticle

Associations of Biopterins and ADMA with Vascular Function in Peripheral Microcirculation from Patients with Chronic Kidney Disease

by Samsul Arefin, Lars Löfgren, Peter Stenvinkel, Anna B. Granqvist and Karolina Kublickiene

Int. J. Mol. Sci. 2023, 24(6), 5582; https://doi.org/10.3390/ijms24065582 - 15 Mar 2023

Viewed by 1323

Abstract

We hypothesized that patients with chronic kidney disease (CKD) display an altered plasma amino acid (AA) metabolomic profile that could contribute to abnormal vascular maintenance of peripheral circulation in uremia. The relationships between plasma AAs and endothelial and vascular smooth muscle function in the microcirculation of CKD patients are not well understood. The objective of this study is to investigate to what extent the levels of AAs and its metabolites are changed in CKD patients and to test their relationship with endothelial and vascular smooth muscle function. Patients with CKD stages 3 and 5 and non-CKD controls are included in this study. We report that there was a significant reduction of the biopterin (BH₄/BH₂) ratio, which was accompanied by increased plasma levels of BH₂, asymmetric dimethylarginine (ADMA) and citrulline in patients with CKD-5 vs. CKD-3 vs. controls. In vivo augmentation index measurement showed a positive association with ADMA in all participants. The contribution of nitric oxide, assessed by ex vivo assay, showed a negative association with creatinine, ADMA and citrulline in all participants. In CKD-5, BH₄ negatively correlated with ADMA and ornithine levels, and the ex vivo endothelium-mediated dilatation positively correlated with phenylalanine levels. In conclusion, uremia is associated with alterations in AA metabolism that may affect endothelium-dependent dilatation and vascular stiffness in microcirculation. Interventional strategies aiming to normalize the AA metabolism could be of interest as treatment options. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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13 pages, 2273 KiB

Open AccessArticle

Role of Klotho and AGE/RAGE-Wnt/β-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes

by Beatriz Martín-Carro, Julia Martín-Vírgala, Sara Fernández-Villabrille, Alejandra Fernández-Fernández, Marcos Pérez-Basterrechea, Juan F. Navarro-González, Javier Donate-Correa, Carmen Mora-Fernández, Adriana S. Dusso, Natalia Carrillo-López, Sara Panizo, Manuel Naves-Díaz, José L. Fernández-Martín, Jorge B. Cannata-Andía and Cristina Alonso-Montes

Int. J. Mol. Sci. 2023, 24(6), 5241; https://doi.org/10.3390/ijms24065241 - 9 Mar 2023

Cited by 8 | Viewed by 2279

Abstract

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, markers of fibrosis (collagen deposition, fibronectin, TGF-β1, and Wnt/β-catenin pathway), hypertrophy of the kidney and/or heart were analysed. At the end of study, diabetic rats showed higher levels of urinary sKlotho, AGEs and sRAGE and lower serum sKlotho compared with controls without differences in the renal Klotho expression. A significant positive correlation was found between urinary sKlotho and AGEs and urinary albumin/creatinine ratio (uACR). Fibrosis and RAGE levels were significantly higher in the heart without differences in the kidney of diabetic rats compared to controls. The results also suggest the increase in sKlotho and sRAGE excretion may be due to polyuria in the diabetic rats. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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13 pages, 1929 KiB

Open AccessArticle

Gut-Derived Uremic Toxins in CKD: An Improved Approach for the Evaluation of Serum Indoxyl Sulfate in Clinical Practice

by Gianvito Caggiano, Loredana Amodio, Alessandra Stasi, Nicola Antonio Colabufo, Santina Colangiulo, Francesco Pesce and Loreto Gesualdo

Int. J. Mol. Sci. 2023, 24(6), 5142; https://doi.org/10.3390/ijms24065142 - 7 Mar 2023

Cited by 2 | Viewed by 1799

Abstract

In the past years, indoxyl sulfate has been strongly implicated in kidney disease progression and contributed to cardiovascular morbidity. Moreover, as a result of its elevated albumin affinity rate, indoxyl sulfate is not adequately cleared by extracorporeal therapies. Within this scenario, although LC-MS/MS represents the conventional approach for IS quantification, it requires dedicated equipment and expert skills and does not allow real-time analysis. In this pilot study, we implemented a fast and simple technology designed to determine serum indoxyl sulfate levels that can be integrated into clinical practice. Indoxyl sulfate was detected at the time of enrollment by Tandem MS from 25 HD patients and 20 healthy volunteers. Next, we used a derivatization reaction to transform the serum indoxyl sulfate into Indigo blue. Thanks to the spectral shift to blue, its quantity was measured by the colorimetric assay at a wavelength of 420–450 nm. The spectrophotometric analysis was able to discriminate the levels of IS between healthy subjects and HD patients corresponding to the LC-MS/MS. In addition, we found a strong linear relationship between indoxyl sulfate levels and Indigo levels between the two methods (Tandem MS and spectrophotometry). This innovative method in the assessment of gut-derived indoxyl sulfate could represent a valid tool for clinicians to monitor CKD progression and dialysis efficacy. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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14 pages, 1985 KiB

Open AccessArticle

Indoxyl Sulphate Retention Is Associated with Microvascular Endothelial Dysfunction after Kidney Transplantation

by Sam Hobson, Samsul Arefin, Awahan Rahman, Leah Hernandez, Thomas Ebert, Henriette de Loor, Pieter Evenepoel, Peter Stenvinkel and Karolina Kublickiene

Int. J. Mol. Sci. 2023, 24(4), 3640; https://doi.org/10.3390/ijms24043640 - 11 Feb 2023

Cited by 3 | Viewed by 1500

Abstract

Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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14 pages, 1424 KiB

Open AccessArticle

The Soluble Fms-like Tyrosine Kinase-1 Contributes to Structural and Functional Changes in Endothelial Cells in Chronic Kidney Disease

by Annika Schulz, Carolin Christina Drost, Bettina Hesse, Katrin Beul, Marcus Brand and Giovana Seno Di Marco

Int. J. Mol. Sci. 2022, 23(24), 16059; https://doi.org/10.3390/ijms232416059 - 16 Dec 2022

Cited by 5 | Viewed by 1234

Abstract

Endothelial cells are a critical target of the soluble Fms-like tyrosine kinase-1 (sFlt-1), a soluble factor increased in different diseases with varying degrees of renal impairment and endothelial dysfunction, including chronic kidney disease (CKD). Although the mechanisms underlying endothelial dysfunction are multifactorial and complex, herein, we investigated the damaging effects of sFlt-1 on structural and functional changes in endothelial cells. Our results evidenced that sera from patients with CKD stiffen the endothelial cell cortex in vitro, an effect correlated with sFlt-1 levels and prevented by sFlt-1 neutralization. Besides, we could show that recombinant sFlt-1 leads to endothelial stiffening in vitro and in vivo. This was accompanied by cytoskeleton reorganization and changes in the endothelial barrier function, as observed by increased actin polymerization and endothelial cell permeability, respectively. These results depended on the activation of the p38 MAPK and were blocked by the specific inhibitor SB203580. However, sFlt-1 only minimally affected the expression of stiffness-sensitive genes. These findings bring new insight into the mechanism of action of sFlt-1 and its biological effects that cannot be exclusively ascribed to the regulation of angiogenesis. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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14 pages, 2674 KiB

Open AccessArticle

Calcitriol Reduces the Inflammation, Endothelial Damage and Oxidative Stress in AKI Caused by Cisplatin

by Beatriz M. Oliveira, Lucas Ferreira de Almeida, Amanda L. Deluque, Claudia S. Souza, Ana Lívia D. Maciel, Heloísa D. C. Francescato, Roberto S. Costa, Cleonice Giovanini, Francisco José A. de Paula and Terezila M. Coimbra

Int. J. Mol. Sci. 2022, 23(24), 15877; https://doi.org/10.3390/ijms232415877 - 14 Dec 2022

Cited by 2 | Viewed by 1786

Abstract

Cisplatin treatment is one of the most commonly used treatments for patients with cancer. However, thirty percent of patients treated with cisplatin develop acute kidney injury (AKI). Several studies have demonstrated the effect of bioactive vitamin D or calcitriol on the inflammatory process and endothelial injury, essential events that contribute to changes in renal function and structure caused by cisplatin (CP). This study explored the effects of calcitriol administration on proximal tubular injury, oxidative stress, inflammation and vascular injury observed in CP-induced AKI. Male Wistar Hannover rats were pretreated with calcitriol (6 ng/day) or vehicle (0.9% NaCl). The treatment started two weeks before i.p. administration of CP or saline and was maintained for another five days after the injections. On the fifth day after the injections, urine, plasma and renal tissue samples were collected to evaluate renal function and structure. The animals of the CP group had increased plasma levels of creatinine and of fractional sodium excretion and decreased glomerular filtration rates. These changes were associated with intense tubular injury, endothelial damage, reductions in antioxidant enzymes and an inflammatory process observed in the renal outer medulla of the animals from this group. These changes were attenuated by treatment with calcitriol, which reduced the inflammation and increased the expression of vascular regeneration markers and antioxidant enzymes. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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10 pages, 1096 KiB

Open AccessArticle

The Utility of Novel Kidney Injury Biomarkers in Early Detection of CSA-AKI

by Jakub Udzik, Aleksandra Waszczyk, Iwona Wojciechowska-Koszko, Paweł Kwiatkowski, Paulina Roszkowska, Karolina Rogulska, Krzysztof Safranow, Andrzej Biskupski, Sebastian Kwiatkowski and Ewa Kwiatkowska

Int. J. Mol. Sci. 2022, 23(24), 15864; https://doi.org/10.3390/ijms232415864 - 14 Dec 2022

Cited by 1 | Viewed by 1524

Abstract

Cardiac surgery-associated acute kidney injury (CSA-AKI) is one of the most common complications of cardiac surgery procedures. In this study, the authors attempt to provide new data regarding the application of novel kidney injury biomarkers in the early diagnostics of CSA-AKI. 128 adult patients undergoing elective cardiac surgery procedures with the use of cardiopulmonary by-pass (CPB) were enrolled in this study. Novel kidney injury biomarkers were marked in the plasma and urine 6 h after weaning from the CPB. A significant difference in the postoperative biomarkers’ concentration between the AKI and no-AKI group was found, regarding plasma IL-8, plasma TNF-α and urine NGAL, normalized for creatinine excretion (NGAL/Cr). These were also independent predictors of CSA-AKI. An independent risk factor for CSA-AKI proved to be preoperative CKD. Plasma IL-8 and TNF-α, as well as urine NGAL/Cr, are independent early indicators of CSA-AKI and pose a promising alternative for creatinine measurements. The cut-off points for these biomarkers proposed in this investigation should be confronted with more data and revised to achieve a suitable diagnostic value. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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14 pages, 2353 KiB

Open AccessArticle

A Dietary Supplement Containing Fucoidan Preserves Endothelial Glycocalyx through ERK/MAPK Signaling and Protects against Damage Induced by CKD Serum

by Manuel Regier, Carolin Christina Drost, Matthias Rauen, Hermann Pavenstädt, Alexandros Rovas, Philipp Kümpers, Hans Vink, Robert M. Long, Wolfgang A. Linke, Jerzy-Roch Nofer and Alexander-Henrik Lukasz

Int. J. Mol. Sci. 2022, 23(24), 15520; https://doi.org/10.3390/ijms232415520 - 8 Dec 2022

Cited by 4 | Viewed by 2576

Abstract

(1) Damage to the endothelial glycocalyx (eGC), a protective layer lining the endothelial luminal surface, is associated with chronic kidney disease (CKD), which leads to a worsening of cardiovascular outcomes in these patients. Currently, there are no targeted therapeutic approaches. Whether the dietary supplement Endocalyx^TM (ECX) protects against endothelial damage caused by uremic toxins is unknown. (2) We addressed this question by performing atomic force microscopy measurements on living endothelial cells. We examined the effect of ECX on eGC thickness at baseline and with pooled serum from hemodialysis patients. ECX was also successfully administered in vivo in mice, in which eGC was assessed using perfused boundary region measurements by intravital microscopy of cremasteric vessels. (3) Both ECX and fucoidan significantly improved baseline eGC thickness. Our data indicate that these effects are dependent on ERK/MAPK and PI3K signaling. After incubation with eGC damaging serum from dialysis patients, ECX increased eGC height. Intravital microscopy in mice revealed a relevant increase in baseline eGC dimensions after feeding with ECX. (4) We identified a dietary supplement containing glycocalyx substrates and fucoidan as potential mediators of eGC preservation in vitro and in vivo. Our findings suggest that fucoidan may be an essential component responsible for protecting the eGC in acute settings. Moreover, ECX might contribute to both protection and rebuilding of the eGC in the context of CKD. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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16 pages, 3947 KiB

Open AccessArticle

Ginsenoside Compound K Ameliorates Development of Diabetic Kidney Disease through Inhibiting TLR4 Activation Induced by Microbially Produced Imidazole Propionate

by Qian Chen, Dongwen Ren, Luokun Liu, Jingge Xu, Yuzheng Wu, Haiyang Yu, Mengyang Liu, Yi Zhang and Tao Wang

Int. J. Mol. Sci. 2022, 23(21), 12863; https://doi.org/10.3390/ijms232112863 - 25 Oct 2022

Cited by 7 | Viewed by 1651

Abstract

Diabetic kidney disease (DKD) is a common and devastating complication in diabetic patients, which is recognized as a large and growing problem leading to end-stage kidney disease. As dietary-mediated therapies are gradually becoming more acceptable to patients with DKD, we planned to find active compounds on preventing DKD progression from dietary material. The present paper reports the renoprotective properties and underlying mechanisms of ginsenoside compound K (CK), a major metabolite in serum after oral administration of ginseng. CK supplementation for 16 weeks could improve urine microalbumin, the ratio of urinary albumin/creatinine and renal morphological abnormal changes in db/db mice. In addition, CK supplementation reshaped the gut microbiota by decreasing the contents of Bacteroides and Paraprevotella and increasing the contents of Lactobacillu and Akkermansia at the genus level, as well as reduced histidine-derived microbial metabolite imidazole propionate (IMP) in the serum. We first found that IMP played a significant role in the progression of DKD through activating toll-like receptor 4 (TLR4). We also confirmed CK supplementation can down-regulate IMP-induced protein expression of the TLR4 signaling pathway in vivo and in vitro. This study suggests that dietary CK could offer a better health benefit in the early intervention of DKD. From a nutrition perspective, CK or dietary material containing CK can possibly be developed as new adjuvant therapy products for DKD. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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Review

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17 pages, 1047 KiB

Open AccessReview

Metalloporphyrins as Tools for Deciphering the Role of Heme Oxygenase in Renal Immune Injury

by Elias A. Lianos and Maria G. Detsika

Int. J. Mol. Sci. 2023, 24(7), 6815; https://doi.org/10.3390/ijms24076815 - 6 Apr 2023

Cited by 1 | Viewed by 1419

Abstract

Renal immune injury is a frequent cause of end-stage renal disease, and, despite the progress made in understanding underlying pathogenetic mechanisms, current treatments to preserve renal function continue to be based mainly on systemic immunosuppression. Small molecules, naturally occurring biologic agents, show considerable promise in acting as disease modifiers and may provide novel therapeutic leads. Certain naturally occurring or synthetic Metalloporphyrins (Mps) can act as disease modifiers by increasing heme oxygenase (HO) enzymatic activity and/or synthesis of the inducible HO isoform (HO-1). Depending on the metal moiety of the Mp employed, these effects may occur in tandem or can be discordant (increased HO-1 synthesis but inhibition of enzyme activity). This review discusses effects of Mps, with varying redox-active transitional metals and cyclic porphyrin cores, on mechanisms underlying pathogenesis and outcomes of renal immune injury. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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13 pages, 2739 KiB

Open AccessReview

sFlt-1 in Chronic Kidney Disease: Friend or Foe?

by Masaru Matsui, Kenji Onoue and Yoshihiko Saito

Int. J. Mol. Sci. 2022, 23(22), 14187; https://doi.org/10.3390/ijms232214187 - 16 Nov 2022

Viewed by 2762

Abstract

Placental growth factor (PlGF) and its receptor, fms-like tyrosine kinase-1 (Flt-1), are important regulators involved in angiogenesis, atherogenesis, and inflammation. This review article focuses on the function of PlGF/Flt-1 signaling and its regulation by soluble Flt-1 (sFlt-1) in chronic kidney disease (CKD). Elevation of circulating sFlt-1 and downregulation of sFlt-1 in the vascular endothelium by uremic toxins and oxidative stress both exacerbate heart failure and atherosclerosis. Circulating sFlt-1 is inconsistent with sFlt-1 synthesis, because levels of matrix-bound sFlt-1 are much higher than those of circulating sFlt-1, as verified by a heparin loading test, and are drastically reduced in CKD. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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Other

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10 pages, 6514 KiB

Open AccessBrief Report

Alterations in Kidney Structures Caused by Age Vary According to Sex and Dehydration Condition

by Susana Quirós Cognuck, Lucas Ferreira de Almeida, Wagner L. Reis, Márcia S. Silva, Gislaine Almeida-Pereira, Sandra V. Zorro, André S. Mecawi, Terezila Machado Coimbra, Lucila L. K. Elias and José Antunes-Rodrigues

Int. J. Mol. Sci. 2022, 23(24), 15672; https://doi.org/10.3390/ijms232415672 - 10 Dec 2022

Cited by 2 | Viewed by 1259

Abstract

Aging is a complex biological process, resulting in gradual and progressive decline in structure and function in many organ systems. Our objective is to determine if structural changes produced by aging vary with sex in a stressful situation such as dehydration. The expression of Slc12a3 mRNA in the renal cortex, α-smooth muscle actin (α-SMA), and fibronectin was evaluated in male and female rats, aged 3 and 18 months, submitted and not submitted to water deprivation (WD) for 48 h, respectively. When comparing ages, 18-month-old males showed a lower expression of Slc12a3 mRNA than 3-month-old males, and control and WD 18-month-old male and female rats exhibited a higher expression of α-SMA than the respective 3-month-old rats. Fibronectin was higher in both control and WD 18-month-old males than the respective 3-month-old males. In females, only the control 18-month-old rats showed higher fibronectin than the control 3-month-old rats. When we compared sex, control and WD 3-month-old female rats had a lower expression of Slc12a3 mRNA than the respective males. The WD 18-month-old male rats presented a higher expression of fibronectin and α-SMA than the WD 18-month-old female rats. When we compared hydric conditions, the WD 18-month-old males displayed a lower relative expression of Slc12a3 mRNA and higher α-SMA expression than the control 18-month-old males. Aging, sex, and dehydration lead to alterations in kidney structure. Full article

(This article belongs to the Special Issue Renal Dysfunction, Uremic Compounds, and Other Factors)

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