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Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 13771

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Special Issue Editor

Dr. Henrik H. Hansen

E-Mail Website
Guest Editor

Gubra, DK-2970 Hoersholm, Denmark
Interests: chronic kidney disease; diabetic kidney disease; pharmacology; animal models; clinical translational research; preclinical research; drug discovery; target discovery

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a major global health problem for which there are no curative drug treatments. CKD is an umbrella term for various renal diseases. Notably, several metabolic risk factors such as diabetes, obesity, dyslipidemia and hypertension are common integral components of CKD. Even in its early stages, CKD is associated with cardiovascular complications and increased mortality, with a marked progressive increase in attributable risk as renal function continues to decline towards end-stage kidney disease.

While SGLT2 inhibitors and GLP-1 receptor agonists are emerging as promising treatment options in CKD with diabetes as the primary cause (diabetic kidney disease), improved understanding of molecular signaling pathways involved in the onset and progression of renal disease in CKD is critical for developing novel and more effective treatments of CKD. In preclinical research, several rodent models are available for investigating the pathophysiology of CKD and testing of novel therapeutic modalities. While current models of CKD are instrumental in preclinical drug screening and target discovery, there is an increasing need for improved preclinical models that more closely mimic the sequelae of CKD. In particular, the use of translational models of CKD is advantageous in the transition from preclinical to clinical drug development.

The goal of this Special Issue is to highlight recent advances in CKD research, with special emphasis on translational animal models of CKD and molecular mechanisms which could potentially be targeted to improve outcomes in CKD.

Based on your expertise in this field, we would be happy to receive your manuscripts related to the topic.

Dr. Henrik H. Hansen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

chronic kidney disease
diabetic kidney disease
renal fibrosis
animal models
model validation
clinical translatability
drug development
drug targets
molecular biology
pharmacology

Published Papers (5 papers)

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Research

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12 pages, 1276 KiB

Open AccessArticle

Combination Therapy of RAS Inhibition and SGLT2 Inhibitors Decreases Levels of Endotrophin in Persons with Type 2 Diabetes

by Alexandra Louise Møller, Stefanie Thöni, Felix Keller, Samir Sharifli, Daniel Guldager Kring Rasmussen, Federica Genovese, Morten Asser Karsdal and Gert Mayer

Biomedicines 2023, 11(11), 3084; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11113084 - 17 Nov 2023

Viewed by 1269

Abstract

We investigated for the first time the effect of combination therapy of renin–angiotensin system inhibition (RASi) and sodium–glucose co-transporter-2 inhibitors (SGLT2is) on endotrophin (ETP), a pro-fibrotic signaling molecule reflecting collagen type VI formation, measured in the plasma of persons with type 2 diabetes (T2D). ETP was measured using the PRO-C6 ELISA in 294 individuals from the “Drug combinations for rewriting trajectories of renal pathologies in type 2 diabetes” (DC-ren) project. In the DC-ren study, kidney disease progression was defined as a >10% decline in the estimated glomerular filtration rate (eGFR) to an eGFR < 60 mL/min/1.73 m². Among the investigated circulating markers, ETP was the most significant predictor of future eGFR. Combination therapy of RASi and SGLT2is led to a significant reduction in ETP levels compared to RASi monotherapy (p for slope difference = 0.002). Higher levels of baseline plasma ETP were associated with a significantly increased risk of kidney disease progression (p = 0.007). In conclusion, plasma ETP identified individuals at higher risk of kidney disease progression. The observed decreased levels of plasma ETP with combination therapy of RASi and SGLT2is in persons with T2D may reflect a reduced risk of kidney disease progression following treatment with SGLT2is. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease)

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22 pages, 1911 KiB

Open AccessArticle

Urate Transporter 1 Can Be a Therapeutic Target Molecule for Chronic Kidney Disease and Diabetic Kidney Disease: A Retrospective Longitudinal Study

by Hidekatsu Yanai, Hisayuki Katsuyama, Mariko Hakoshima and Hiroki Adachi

Biomedicines 2023, 11(2), 567; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11020567 - 15 Feb 2023

Cited by 6 | Viewed by 3246

Abstract

Chronic kidney disease (CKD) is a major global health problem for which there are no curative drug treatments. Hyperuricemia is one of risk factors for CKD. The evidence on effects of uric acid (UA)-lowering treatments on the progression of CKD was very limited and previous meta-analyses used only trials which primarily used xanthin oxidase (XO) inhibitors because the reports on fulminant hepatitis due to benzbromarone kept us from using uricosuric agents for hyperuricemia patients. Dotinurad, a novel selective urate reabsorption inhibitor for the treatment of hyperuricemia, reduces serum UA levels by selectively inhibiting urate transporter 1 (URAT1). We retrospectively picked up patients who had taken dotinurad from June 2018 to August 2021 and compared metabolic parameters at baseline with the data at 3 and 6 months after the start of dotinurad. We found 84 patients, and approximately 74% of patients were complicated with CKD. After the start of dotinurad, improvements in serum lipids, systolic blood pressure, body weight, and albuminuria, in addition to reduction in serum UA, were observed. Dotinurad increased urinary UA excretion, and was effective to reduce serum UA in patients with both UA underexcretion type and renal UA overload type. Furthermore, urinary UA excretion was significantly and negatively correlated with serum creatine levels at baseline and at 6 months after the start of dotinurad, and the change in urinary UA excretion after 3 months was significantly and negatively correlated with change in serum creatine levels. The property of dotinurad, which selectively inhibits URAT1, but not other UA transporters, such as ATP-binding cassette, subfamily G, and 2 (ABCG2), which ABCG2 is a UA and uremic toxin exporter, may be beneficially associated with pathology of CKD. URAT1 can be a therapeutic target molecule for CKD and DKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease)

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Review

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21 pages, 345 KiB

Open AccessReview

Transforming Diabetes Care: The Molecular Pathways through Which GLP1-RAs Impact the Kidneys in Diabetic Kidney Disease

by Merita Rroji and Goce Spasovski

Biomedicines 2024, 12(3), 657; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines12030657 - 14 Mar 2024

Viewed by 1343

Abstract

Diabetic kidney disease (DKD) is a substantial complication of type 2 diabetes (T2D), presenting challenges in chronic kidney disease (CKD) management. In addition to traditional and recent therapies, including angiotensin, converting enzyme (ACE) inhibitors, angiotensin receptor blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists, the evolution of antihyperglycemic treatments has introduced a promising agent, glucagon-like peptide-1 receptor agonist (GLP-1RA) for the management of DKD. GLP-1RAs enhance insulin release and reduce glucagon release, offering a novel approach to DKD management. This review analyzes the molecular pathways through which GLP1-RAs confer renal protection in T2D and DKD, which are complex and multifaceted. They include modulation of renal hemodynamics, antioxidative and anti-inflammatory actions, metabolic regulation, and direct cellular effects. These mechanisms highlight GLP1-RA’s potential as a therapeutic option for glycemic control and direct or indirect renal function protection in diabetic patients, emphasizing the potentiality of GLP-1RAs for dual therapy, with cardiovascular and renal protection as a holistic approach. Clinical evidence supports GLP-1RAs in reducing albuminuria and enhancing kidney outcomes, highlighting their value in a comprehensive DKD management strategy. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease)

18 pages, 703 KiB

Open AccessReview

Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes

by Kranti A. Mapuskar, Gabriela Vasquez-Martinez, Gabriel Mayoral-Andrade, Ann Tomanek-Chalkley, Diana Zepeda-Orozco and Bryan G. Allen

Biomedicines 2023, 11(6), 1573; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11061573 - 29 May 2023

Cited by 4 | Viewed by 2283

Abstract

Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O₂^●−) and hydrogen peroxide (H₂O₂). Increased O₂^●− and H₂O₂ may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease)

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21 pages, 1174 KiB

Open AccessReview

Physiological Associations between Vitamin B Deficiency and Diabetic Kidney Disease

by Henry H. L. Wu, Thomas McDonnell and Rajkumar Chinnadurai

Biomedicines 2023, 11(4), 1153; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11041153 - 11 Apr 2023

Cited by 2 | Viewed by 4912

Abstract

The number of people living with chronic kidney disease (CKD) is growing as our global population continues to expand. With aging, diabetes, and cardiovascular disease being major harbingers of kidney disease, the number of people diagnosed with diabetic kidney disease (DKD) has grown concurrently. Poor clinical outcomes in DKD could be influenced by an array of factors—inadequate glycemic control, obesity, metabolic acidosis, anemia, cellular senescence, infection and inflammation, cognitive impairment, reduced physical exercise threshold, and, importantly, malnutrition contributing to protein-energy wasting, sarcopenia, and frailty. Amongst the various causes of malnutrition in DKD, the metabolic mechanisms of vitamin B (B1 (Thiamine), B2 (Riboflavin), B3 (Niacin/Nicotinamide), B5 (Pantothenic Acid), B6 (Pyridoxine), B8 (Biotin), B9 (Folate), and B12 (Cobalamin)) deficiency and its clinical impact has garnered greater scientific interest over the past decade. There remains extensive debate on the biochemical intricacies of vitamin B metabolic pathways and how their deficiencies may affect the development of CKD, diabetes, and subsequently DKD, and vice-versa. Our article provides a review of updated evidence on the biochemical and physiological properties of the vitamin B sub-forms in normal states, and how vitamin B deficiency and defects in their metabolic pathways may influence CKD/DKD pathophysiology, and in reverse how CKD/DKD progression may affect vitamin B metabolism. We hope our article increases awareness of vitamin B deficiency in DKD and the complex physiological associations that exist between vitamin B deficiency, diabetes, and CKD. Further research efforts are needed going forward to address the knowledge gaps on this topic. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Novel Therapies for Chronic Kidney Disease: Focus on Diabetic Kidney Disease)

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