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Molecular Mechanisms Involved in Diabetic Nephropathy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 74874

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Special Issue Editors

Prof. Dr. Jesus Egido

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Renal, Vascular and Diabetes Research Laboratory. Fundacion Jimenez Diaz University Hospital-Health Research Institute (FIIS-FJD), Autonoma University of Madrid (UAM), 28040 Madrid, Spain;

Prof. Dr. Carmen Gómez-Guerrero

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Renal, Vascular and Diabetes Research Laboratory. CIBERDEM. University Hospital Fundacion Jimenez Diaz, Madrid, Spain

Dr. Juan Antonio Moreno

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Department of Cell Biology, Physiology, and Immunology, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, Cordoba, Spain
Interests: pathophysiology of renal damage; acute kidney injury and chronic kidney disease
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Special Issue Information

Dear Colleagues,

Diabetic Nephropathy (DN) is a major microvascular complication of diabetes. The epidemic increase of type 2 diabetes is the main cause of chronic kidney disease (CKD) worldwide, leading to premature death and end-stage renal disease (ESRD). Management of DN focuses on the intensive glycemic control and treatment of hypertension, mainly by inhibition of the renin–angiotensin–aldosterone system that delays the onset and progression of DN but does not reduce the risk of ESRD in many patients. During the last few years, tremendous advances have been made concerning the cellular and molecular mechanisms involved in kidney damage during the diabetic process. Although new antidiabetic drugs possess markedly cardiovascular and renal protective effects, it is necessary to increase the knowledge of the molecular mechanisms involved in this pathology to develop novel therapies.

This Special Issue on “Molecular mechanisms involved in Diabetic Nephropathy” will include papers investigating the pathological mechanisms involved in diabetic nephropathy, and diagnostics using new biomarkers. Furthermore, experimental in vitro and in vivo studies and clinical studies examining potential new approaches to attenuate kidney dysfunction are welcome.

This Special Issue welcomes original research and review papers. Potential topics include but are not limited to the topics suggested by the keywords below.

Prof. Dr. Jesus Egido
Prof. Dr. Carmen Gómez-Guerrero
Dr. Juan Antonio Moreno Gutierrez
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Experimental models of diabetic nephropathy
Oxidative stress and inflammation
NLRP inflammasome
Cytokines, adipokines, chemokines, and interleukins
Mitochondrial dysfunction
Cell signaling
Autophagy and Senescence
Lipotoxicity
Gut microbiome
Epigenetics
System Biology, proteomics and miRNAs
Systemic and urinary biomarkers
Podocyte dysfunction
Epithelial to mesenchymal transition in DN
Flavonoids and herbal medicine
Novel therapeutic approaches

Published Papers (10 papers)

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Research

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22 pages, 7694 KiB

Open AccessArticle

Therapeutic Potential of Mesenchymal Stem Cells in a Pre-Clinical Model of Diabetic Kidney Disease and Obesity

by Christian Sávio-Silva, Poliana E. Soinski-Sousa, Antônio Simplício-Filho, Rosana M. C. Bastos, Stephany Beyerstedt and Érika Bevilaqua Rangel

Int. J. Mol. Sci. 2021, 22(4), 1546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041546 - 04 Feb 2021

Cited by 17 | Viewed by 3182

Abstract

Diabetic kidney disease (DKD) is a worldwide microvascular complication of type 2 diabetes mellitus (T2DM). From several pathological mechanisms involved in T2DM-DKD, we focused on mitochondria damage induced by hyperglycemia-driven reactive species oxygen (ROS) accumulation and verified whether mesenchymal stem cells (MSCs) anti-oxidative, anti-apoptotic, autophagy modulation, and pro-mitochondria homeostasis therapeutic potential curtailed T2DM-DKD progression. For that purpose, we grew immortalized glomerular mesangial cells (GMCs) in hyper glucose media containing hydrogen peroxide. MSCs prevented these cells from apoptosis-induced cell death, ROS accumulation, and mitochondria membrane potential impairment. Additionally, MSCs recovered GMCs’ biogenesis and mitophagy-related gene expression that were downregulated by stress media. In BTBR^ob/ob mice, a robust model of T2DM-DKD and obesity, MSC therapy (1 × 10⁶ cells, two doses 4-weeks apart, intra-peritoneal route) led to functional and structural kidney improvement in a time-dependent manner. Therefore, MSC-treated animals exhibited lower levels of urinary albumin-to-creatinine ratio, less mesangial expansion, higher number of podocytes, up-regulation of mitochondria-related survival genes, a decrease in autophagy hyper-activation, and a potential decrease in cleaved-caspase 3 expression. Collectively, these novel findings have important implications for the advancement of cell therapy and provide insights into cellular and molecular mechanisms of MSC-based therapy in T2DM-DKD setting. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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17 pages, 4824 KiB

Open AccessArticle

Targeting NF-κB by the Cell-Permeable NEMO-Binding Domain Peptide Improves Albuminuria and Renal Lesions in an Experimental Model of Type 2 Diabetic Nephropathy

by Lucas Opazo-Ríos, Anita Plaza, Yenniffer Sánchez Matus, Susana Bernal, Laura Lopez-Sanz, Luna Jimenez-Castilla, Daniel Carpio, Alejandra Droguett, Sergio Mezzano, Jesús Egido and Carmen Gomez-Guerrero

Int. J. Mol. Sci. 2020, 21(12), 4225; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124225 - 13 Jun 2020

Cited by 10 | Viewed by 2971

Abstract

Diabetic nephropathy (DN) is a multifactorial disease characterized by hyperglycemia and close interaction of hemodynamic, metabolic and inflammatory factors. Nuclear factor-κB (NF-κB) is a principal matchmaker linking hyperglycemia and inflammation. The present work investigates the cell-permeable peptide containing the inhibitor of kappa B kinase γ (IKKγ)/NF-κB essential modulator (NEMO)-binding domain (NBD) as therapeutic option to modulate inflammation in a preclinical model of type 2 diabetes (T2D) with DN. Black and tan, brachyuric obese/obese mice were randomized into 4 interventions groups: Active NBD peptide (10 and 6 µg/g body weight); Inactive mutant peptide (10 µg/g); and vehicle control. In vivo/ex vivo fluorescence imaging revealed efficient delivery of NBD peptide, systemic biodistribution and selective renal metabolization. In vivo administration of active NBD peptide improved albuminuria (>40% reduction on average) and kidney damage, decreased podocyte loss and basement membrane thickness, and modulated the expression of proinflammatory and oxidative stress markers. In vitro, NBD blocked IKK-mediated NF-κB induction and target gene expression in mesangial cells exposed to diabetic-like milieu. These results constitute the first nephroprotective effect of NBD peptide in a T2D mouse model that recapitulates the kidney lesions observed in DN patients. Targeting IKK-dependent NF-κB activation could be a therapeutic strategy to combat kidney inflammation in DN. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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Review

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20 pages, 943 KiB

Open AccessReview

Molecular Mechanisms in Early Diabetic Kidney Disease: Glomerular Endothelial Cell Dysfunction

by Emelie Lassén and Ilse S. Daehn

Int. J. Mol. Sci. 2020, 21(24), 9456; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249456 - 11 Dec 2020

Cited by 63 | Viewed by 9443

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), with prevalence increasing at an alarming rate worldwide and today, there are no known cures. The pathogenesis of DKD is complex, influenced by genetics and the environment. However, the underlying molecular mechanisms that contribute to DKD risk in about one-third of diabetics are still poorly understood. The early stage of DKD is characterized by glomerular hyperfiltration, hypertrophy, podocyte injury and depletion. Recent evidence of glomerular endothelial cell injury at the early stage of DKD has been suggested to be critical in the pathological process and has highlighted the importance of glomerular intercellular crosstalk. A potential mechanism may include reactive oxygen species (ROS), which play a direct role in diabetes and its complications. In this review, we discuss different cellular sources of ROS in diabetes and a new emerging paradigm of endothelial cell dysfunction as a key event in the pathogenesis of DKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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26 pages, 1390 KiB

Open AccessReview

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

by Julio M. Martinez-Moreno, Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Juan Guerrero-Mauvecin, Elena Goma-Garces, Beatriz Fernandez-Fernandez, Sol Carriazo, Maria D. Sanchez-Niño, Adrian M. Ramos, Marta Ruiz-Ortega, Alberto Ortiz and Ana B. Sanz

Int. J. Mol. Sci. 2020, 21(11), 4113; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114113 - 09 Jun 2020

Cited by 40 | Viewed by 5663

Abstract

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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40 pages, 2296 KiB

Open AccessReview

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

by Sandra Rayego-Mateos, José Luis Morgado-Pascual, Lucas Opazo-Ríos, Melania Guerrero-Hue, Cristina García-Caballero, Cristina Vázquez-Carballo, Sebastián Mas, Ana Belén Sanz, Carmen Herencia, Sergio Mezzano, Carmen Gómez-Guerrero, Juan Antonio Moreno and Jesús Egido

Int. J. Mol. Sci. 2020, 21(11), 3798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113798 - 27 May 2020

Cited by 155 | Viewed by 11390

Abstract

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several anti-inflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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23 pages, 908 KiB

Open AccessReview

Revisiting Experimental Models of Diabetic Nephropathy

by Anna Giralt-López, Mireia Molina-Van den Bosch, Ander Vergara, Clara García-Carro, Daniel Seron, Conxita Jacobs-Cachá and Maria José Soler

Int. J. Mol. Sci. 2020, 21(10), 3587; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103587 - 19 May 2020

Cited by 46 | Viewed by 8392

Abstract

Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to diabetes of each experimental strain. The classical DN murine models (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all of the typical DN features. For this reason, many models have been crossed to a susceptible genetic background. Knockout and transgenic strains have also been created to generate more robust models. In this review, we will focus on the description of the new DN rodent models and, additionally, we will provide an overview of the available methods for renal phenotyping. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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14 pages, 612 KiB

Open AccessReview

Macrophage Phenotype and Fibrosis in Diabetic Nephropathy

by Priscila Calle and Georgina Hotter

Int. J. Mol. Sci. 2020, 21(8), 2806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082806 - 17 Apr 2020

Cited by 113 | Viewed by 8467

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease globally. The primary initiating mechanism in DN is hyperglycemia-induced vascular dysfunction, but its progression is due to different pathological mechanisms, including oxidative stress, inflammatory cells infiltration, inflammation and fibrosis. Macrophages (Mφ) accumulation in kidneys correlates strongly with serum creatinine, interstitial myofibroblast accumulation and interstitial fibrosis scores. However, whether or not Mφ polarization is involved in the progression of DN has not been adequately defined. The prevalence of the different phenotypes during the course of DN, the existence of hybrid phenotypes and the plasticity of these cells depending of the environment have led to inconclusive results. In the same sense the role of the different macrophage phenotype in fibrosis associated or not to DN warrants additional investigation into Mφ polarization and its role in fibrosis. Due to the association between fibrosis and the progressive decline of renal function in DN, and the role of the different phenotypes of Mφ in fibrosis, in this review we examine the role of macrophage phenotype control in DN and highlight the potential factors contributing to phenotype change and injury or repair in DN. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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30 pages, 2485 KiB

Open AccessReview

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

by Lucas Opazo-Ríos, Sebastián Mas, Gema Marín-Royo, Sergio Mezzano, Carmen Gómez-Guerrero, Juan Antonio Moreno and Jesús Egido

Int. J. Mol. Sci. 2020, 21(7), 2632; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072632 - 10 Apr 2020

Cited by 163 | Viewed by 13199

Abstract

Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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32 pages, 815 KiB

Open AccessReview

Glucose and Blood Pressure-Dependent Pathways–The Progression of Diabetic Kidney Disease

by Devang M. Patel, Madhura Bose and Mark E. Cooper

Int. J. Mol. Sci. 2020, 21(6), 2218; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062218 - 23 Mar 2020

Cited by 33 | Viewed by 7051

Abstract

The major clinical associations with the progression of diabetic kidney disease (DKD) are glycemic control and systemic hypertension. Recent studies have continued to emphasize vasoactive hormone pathways including aldosterone and endothelin which suggest a key role for vasoconstrictor pathways in promoting renal damage in diabetes. The role of glucose per se remains difficult to define in DKD but appears to involve key intermediates including reactive oxygen species (ROS) and dicarbonyls such as methylglyoxal which activate intracellular pathways to promote fibrosis and inflammation in the kidney. Recent studies have identified a novel molecular interaction between hemodynamic and metabolic pathways which could lead to new treatments for DKD. This should lead to a further improvement in the outlook of DKD building on positive results from RAAS blockade and more recently newer classes of glucose-lowering agents such as SGLT2 inhibitors and GLP1 receptor agonists. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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14 pages, 424 KiB

Open AccessReview

Circulating Tumor Necrosis Factor Receptors: A Potential Biomarker for the Progression of Diabetic Kidney Disease

by Maki Murakoshi, Tomohito Gohda and Yusuke Suzuki

Int. J. Mol. Sci. 2020, 21(6), 1957; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061957 - 13 Mar 2020

Cited by 36 | Viewed by 4293

Abstract

Despite considerable advancements in medicine, the optimal treatment for chronic kidney disease (CKD), especially diabetic kidney disease (DKD), remains a major challenge. More patients with DKD succumb to death due to cardiovascular events than due to progression to end-stage renal disease (ESRD). Moreover, patients with DKD and ESRD have remarkably poor prognosis. Current studies have appreciated the contribution of inflammation and inflammatory mediators, such as tumor necrosis factor (TNF)-related biomarkers, on the development/progression of DKD. The present review focuses on molecular roles, serum concentrations of TNF receptors (TNFRs), and their association with increased albuminuria, eGFR decline, and all-cause mortality in diabetes. Experimental studies have suggested that DKD progression occurs through the TNFα–TNFR2 inflammatory pathway. Moreover, serum TNFR levels were positively associated with albuminuria and negatively associated with estimated glomerular filtration rate (eGFR), while circulating levels of TNFRs exhibited an independent effect on all-cause mortality and eGFR decline, including ESRD, even after adjusting for existing risk factors. However, their precise function has yet to be elucidated and requires further studies. Full article

(This article belongs to the Special Issue Molecular Mechanisms Involved in Diabetic Nephropathy)

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