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17 pages, 11552 KiB

Open AccessArticle

Apocynin and Hyperbaric Oxygen Therapy Improve Renal Function and Structure in an Animal Model of CKD

by Andrija Vukovic, Danijela Karanovic, Nevena D Mihailovic-Stanojevic, Zoran Miloradovic, Predrag Brkic, Maja Zivotic, Jelena Nesovic Ostojic, Milan Ivanov, Sanjin Kovacevic, Una-Jovana Vajic, Djurdjica Jovovic and Silvio R. De Luka

Biomedicines 2024, 12(12), 2788; https://doi.org/10.3390/biomedicines12122788 - 9 Dec 2024

Viewed by 1173

Abstract

Background/Objectives: Chronic kidney disease (CKD) is a progressive pathological condition which results in the severe fibrosis of the kidneys. However, the mechanisms of CKD progression and fibrogenesis remain unclear. We wanted to examine the effects that apocynin and hyperbaric oxygen therapy (HBOT) have [...] Read more.

Background/Objectives: Chronic kidney disease (CKD) is a progressive pathological condition which results in the severe fibrosis of the kidneys. However, the mechanisms of CKD progression and fibrogenesis remain unclear. We wanted to examine the effects that apocynin and hyperbaric oxygen therapy (HBOT) have on renal function and structure in animals with CKD induced through 5/6 nephrectomy (5/6 Nx-L). Methods: Male Wistar rats were divided in 5 groups (n = 8/group) as follows: control—sham-operated rats; Nx-L—rats with 5/6 Nx-L; APO—5/6 Nx-L + apocynin treatment; HBOT—5/6 Nx-L + hyperbaric oxygen treatment, and APO+HBOT—5/6 Nx-L, treated with both treatments. All treatments started 4 weeks after the final step of CKD induction and lasted for 4 weeks. At the end of the experiment, urine samples were collected for the proteinuria assessment and the mean arterial pressure (MAP) was measured. Kidneys were collected for histopathological, Western blot, and immunohistochemical analyses. Results: All treatments significantly decreased MAP compared to the Nx-L group (p < 0.001). In the APO and APO+HBOT groups, the level of proteinuria was decreased compared to the Nx-L group (p < 0.05 and p < 0.01, respectively). All examined treatments significantly decreased the intensity of lesions in the kidney compared to those observed in the Nx-L group (p < 0.001). Isolated treatments with apocynin and HBOT induced a significant decrease in desmin expression compared to the Nx-L group (p < 0.05); meanwhile, they did not affect the levels of fibronectin (FN) and hypoxia-inducible factor-1α (HIF-1α). Combined treatment did not affect desmin expression levels; however, it induced a significant increase in fibronectin expression compared to Nx-L (p < 0.001). Conclusions: Apocynin treatment decreased BP and protein loss, and it improved renal morphology at least partly through the downregulation of desmin expression without changing FN and HIF-1α. Hyperbaric oxygen therapy improved hypertension but failed to significantly affect the level of proteinuria. Combined treatment (apocynin and HBOT) normalized blood pressure (BP) values, renal function, and improved kidney structure by modulating FN and HIF-1α, without affecting desmin protein expression. Further studies are needed to elucidate the mechanisms of slowing down the progression of CKD in this experimental model. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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12 pages, 1679 KiB

Open AccessArticle

Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats

by Dong Ho Choi, Su Mi Lee, Bin Na Park, Mi Hwa Lee, Dong Eun Yang, Young Ki Son, Seong Eun Kim and Won Suk An

Biomedicines 2024, 12(9), 2107; https://doi.org/10.3390/biomedicines12092107 - 15 Sep 2024

Viewed by 1369

Abstract

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy [...] Read more.

Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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11 pages, 1273 KiB

Open AccessArticle

The Efficacy and Safety of High-Dose Cholecalciferol Therapy in Hemodialysis Patients

by Agnieszka Tarasewicz, Michał Komorniczak, Agnieszka Zakrzewska, Bogdan Biedunkiewicz, Sylwia Małgorzewicz, Magdalena Jankowska, Katarzyna Jasiulewicz, Natalia Płonka, Małgorzata Dąbrowska, Alicja Dębska-Ślizień and Leszek Tylicki

Biomedicines 2024, 12(2), 377; https://doi.org/10.3390/biomedicines12020377 - 6 Feb 2024

Cited by 1 | Viewed by 1659

Abstract

Vitamin D deficiency and insufficiency are highly prevalent in CKD, affecting over 80% of hemodialysis (HD) patients and requiring therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was [...] Read more.

Vitamin D deficiency and insufficiency are highly prevalent in CKD, affecting over 80% of hemodialysis (HD) patients and requiring therapeutic intervention. Nephrological societies suggest the administration of cholecalciferol according to the guidelines for the general population. The aim of the observational study was to evaluate the efficacy and safety of the therapy with a high dose of cholecalciferol in HD patients with 25(OH)D deficiency and insufficiency to reach the target serum 25(OH)D level > 30 ng/mL. A total of 22 patients (16 M), with an average age of 72.5 ± 13.03 years and 25(OH)D concentration of 13.05 (9.00–17.90) ng/mL, were administered cholecalciferol at a therapeutic dose of 70,000 IU/week (20,000 IU + 20,000 IU + 30,000 IU, immediately after each dialysis session). All patients achieved the target value > 30 ng/mL, with a mean time of 2.86 ± 1.87 weeks. In the first week, the target level of 25(OH)D (100%) was reached by 2 patients (9.09%), in the second week by 15 patients (68.18%), in the fourth week by 18 patients (81.18%), and in the ninth week by all 22 patients (100%). A significant increase in 1,25(OH)₂D levels was observed during the study. However, only 2 patients (9.09%) achieved a concentration of 1,25(OH)₂D above 25 ng/mL—the lower limit of the reference range. The intact PTH concentrations remained unchanged during the observation period. No episodes of hypercalcemia were detected, and one new episode of hyperphosphatemia was observed. In conclusion, our study showed that the administration of a high-therapeutic dose of cholecalciferol allowed for a quick, effective, and safe leveling of 25(OH)D concentration in HD patients. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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13 pages, 2567 KiB

Open AccessArticle

Prognostic Significance of Amino Acid and Biogenic Amines Profiling in Chronic Kidney Disease

by Guillermo Gervasini, Zoraida Verde, Luz M. González, Celia Chicharro, Laura González-Rodríguez, Ana Fernández-Araque, Sonia Mota-Zamorano, Bárbara Cancho, Alberto Pérez-Hernández, Virginio García-López, Fernando Bandrés and Nicolás R. Robles

Biomedicines 2023, 11(10), 2775; https://doi.org/10.3390/biomedicines11102775 - 13 Oct 2023

Cited by 3 | Viewed by 1817

Abstract

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine [...] Read more.

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine a metabolic profile of 28 amino acids (AAs) and biogenic amines to test their value as markers of CKD risk and progression. The kynurenine/tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient = −0.731, p < 0.0001). Models created with orthogonal partial least squares-discriminant analysis (OPLS-DA) containing the metabolic signature showed a high goodness of fit and predictability for controls/CKD (R2X:0.73:R2Y:0.92:Q2:0.92, p < 0.0001) and lower values for CKD/ESKD (R2X:0.56:R2Y:0.59:Q2:0.55, p < 0.0001). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD and CKD/ESKD groups were citrulline (1.63) and tryptophan (1.47), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved the AUC from 86.7% (83.6–89.9) to 100% (100–100) for CKD risk (p < 0.0001) and from 63.0% (58.2–67.8) to 96.5% (95.3–97.8) for the risk of progression from CKD to ESKD (p < 0.0001). Plasma concentrations of AAs and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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Review

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14 pages, 657 KiB

Open AccessReview

The Many Faces of Protease-Activated Receptor 2 in Kidney Injury

by Yuji Oe, Tetsuhiro Tanaka and Nobuyuki Takahashi

Biomedicines 2025, 13(2), 414; https://doi.org/10.3390/biomedicines13020414 - 8 Feb 2025

Viewed by 850

Abstract

Protease-activated receptor 2 (PAR2) is a seven-transmembrane, G-protein-coupled receptor that is activated by coagulation proteases such as factor VIIa and factor Xa and other serine proteases. It is a potential therapeutic target for kidney injury, as it enhances inflammatory and fibrotic responses via [...] Read more.

Protease-activated receptor 2 (PAR2) is a seven-transmembrane, G-protein-coupled receptor that is activated by coagulation proteases such as factor VIIa and factor Xa and other serine proteases. It is a potential therapeutic target for kidney injury, as it enhances inflammatory and fibrotic responses via the nuclear factor-kappa B and mitogen-activated protein kinase cascades. The body of knowledge regarding the role of PAR2 in kidney disease is currently growing, and its role in various kidney disease models, such as acute kidney injury, renal fibrosis, diabetic kidney disease, aging, and thrombotic microangiopathy, has been reported. Here, we review the literature to better understand the various aspects of PAR2 in kidney disease. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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23 pages, 830 KiB

Open AccessReview

Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions

by Rajesh Jha, Sara Lopez-Trevino, Haritha R. Kankanamalage and Jay C. Jha

Biomedicines 2024, 12(5), 1098; https://doi.org/10.3390/biomedicines12051098 - 15 May 2024

Cited by 22 | Viewed by 12700

Abstract

Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of [...] Read more.

Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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22 pages, 1423 KiB

Open AccessReview

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease

by Giacomo Bonacchi, Valentina Alice Rossi, Manuel Garofalo, Rocco Mollace, Giuseppe Uccello, Paolo Pieragnoli, Luca Checchi, Laura Perrotta, Luca Voltolini, Giuseppe Ricciardi and Matteo Beltrami

Biomedicines 2024, 12(5), 981; https://doi.org/10.3390/biomedicines12050981 - 30 Apr 2024

Cited by 3 | Viewed by 2943

Abstract

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological [...] Read more.

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called “kidney tamponade”, explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium–glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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13 pages, 609 KiB

Open AccessReview

The Impact of Physical Exercise on microRNAs in Hemodialysis Patients: A Review and a Protocol for an Ancillary Study

by Rossella Elia, Giovanni Piva, Francesca Bulighin, Nicola Lamberti, Fabio Manfredini, Giovanni Gambaro, Alessio Di Maria, Gianluca Salvagno, Luca Giuseppe Dalle Carbonare, Alda Storari, Maria Teresa Valenti and Yuri Battaglia

Biomedicines 2024, 12(2), 468; https://doi.org/10.3390/biomedicines12020468 - 19 Feb 2024

Cited by 3 | Viewed by 2123

Abstract

Physical inactivity is considered a significant risk factor for mortality and morbidity among chronic hemodialysis (HD) patients. Therefore, physical exercise is recommended in the treatment of HD patients. Although the beneficial effects of physical exercise in HD patients are well-described in the literature, [...] Read more.

Physical inactivity is considered a significant risk factor for mortality and morbidity among chronic hemodialysis (HD) patients. Therefore, physical exercise is recommended in the treatment of HD patients. Although the beneficial effects of physical exercise in HD patients are well-described in the literature, the underlying physiological mechanisms still need to be fully understood. Recently, microRNAs (miRNAs) have emerged as potential mediators of the therapeutic effects of physical exercise in healthy individuals. miRNAs are short, single-stranded, noncoding RNAs involved in gene expression regulation. Specifically, upon forming the RNA-induced silencing complex, miRNAs selectively bind to specific miRNAs within cells, reducing gene expression. miRNAs can be secreted by cells in an accessible form or enclosed within exosomes or extracellular vesicles. They can be detected in various body fluids, including serum (circulating miRNAs), facilitating the study of their diverse expression. Currently, there is no available data regarding the impact of physical exercise on the expression of miRNAs involved in osteogenic differentiation, a fundamental mechanism in the development of vascular calcification, for HD patients. Therefore, we have designed an observational and longitudinal case-control study to evaluate the expression of miR-9 and miR-30b in HD patients participating in a 3-month interdialytic physical exercise program. This paper aims to present the study protocol and review the expression of circulating miRNAs in HD patients and their modulation through physical exercise. Full article

(This article belongs to the Special Issue Pathophysiology of Chronic Kidney Disease and Its Complications, 2nd Edition)

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