Molecular mechanisms and therapeutic targets for diabetic kidney disease

Kidney International, Journal Year: 2022, Volume and Issue: 102(2), P. 248 - 260

Published: June 3, 2022

Diabetic kidney disease has a high global burden and substantially increases the risk of failure cardiovascular events. Despite treatment, there is substantial residual progression with existing therapies. Therefore, an urgent need to better understand molecular mechanisms driving diabetic help identify new therapies that slow reduce associated risks. initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, fibrotic processes contribute progression. This review summarizes evidence on drivers onset progression, focusing inflammatory mediators—factors are largely unaddressed as primary treatment targets for increasing supporting key roles pathophysiology disease. Results from recent clinical trials highlight promising drug therapies, well role dietary strategies, treating Chronic (CKD), characterized albuminuria, low estimated glomerular filtration rate (eGFR), or both,1GBD Kidney Disease CollaborationGlobal, regional, national chronic disease, 1990-2017: systematic analysis Global Burden Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text PDF PubMed Scopus (1156) Google Scholar affect over 840 million people worldwide.2Jager K.J. Kovesdy C. Langham R. et al.A single number advocacy communication-worldwide more than 850 individuals have diseases.Kidney Int. 2019; 96: 1048-1050Abstract (DKD), damage due diabetes, leading attributable cause CKD, occurring approximately 40% type 2 diabetes (T2D) 30% those 1 (T1D).1GBD Scholar,3Alicic R.Z. Rooney M.T. 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Jimenez-Ceja L.M. al.Progressive shifts reflect prediabetes treatment-naive Mexican cohort.Front (Lausanne). 602326Crossref (2) Complex especially essentially "diseases diseases," such present major challenges deciphering reproducible genetic contributions susceptibility severity.47Cole Florez J.C. Genetics complications.Nat 377-390Crossref (163) Advances acquiring large datasets genome-wide association yielded insights shed light predisposition DKD. Missense mutations COL4A3 gene, encodes structural component basement membrane (GBM), known Alport syndrome.48Salem R.M. Todd J.N. Sandholm al.Genome-wide study highlights biology involved collagen.J 30: 2000-2016Crossref Recently, variant (rs55703767) linked "diabetic nephropathy" T1D, suggesting disordered collagen expression.48Salem was most evident glycated hemoglobin. less GBM thickening glomerulosclerosis among either who biopsy data. Thus, "second-hit" phenomenon operative consequences hyperglycemia, damage. Variants genes (DDR1, COLEC11, BMP7) various phenotypes.48Salem contrast variants, APOL-l G1/G2 alleles observed African ancestry nondiabetic often when accompanied "second hit," viral illness interferon state.49Friedman D.J. Pollak M.R. APOL1 genetics applications.Clin 294-303Crossref (11) Another APOL-1 (rs9622363) recently reported meta-analysis American it progression.50Guan Keaton Dimitrov identifies novel loci diabetes-attributed end-stage Americans.Hum Genomics. 13: 21Crossref Among European cohort GABRR1 (rs9942471) highly microalbuminuria.51van Zuydam N.R. Ahlqvist E. subjects diab

Language: Английский

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Signaling pathways of chronic kidney diseases, implications for therapeutics

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: June 9, 2022

Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity oxidative stress are the driving force for loss of including tubules, glomerulus, endothelium. NLRP3 inflammasome signaling, MAPK PI3K/Akt RAAS signaling involves in lipotoxicity. The upregulated Nox expression decreased Nrf2 result directly. injured resident cells release proinflammatory cytokines chemokines to recruit immune such as macrophages from bone marrow. NF-κB JAK-STAT Toll-like receptor cGAS-STING major pathways mediate inflammation inflammatory cells. produce secret great number profibrotic TGF-β1, Wnt ligands, angiotensin II. TGF-β Notch evoke activation promote generation ECM. potential therapies targeted these also introduced here. In this review, we update key lipotoxicity, stress, kidneys with injury, drugs based on latest studies. Unifying will be instrumental advance further basic clinical investigation CKD.

Language: Английский

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Targeting inflammation to treat diabetic kidney disease: the road to 2030

Kidney International, Journal Year: 2022, Volume and Issue: 103(2), P. 282 - 296

Published: Dec. 5, 2022

Language: Английский

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Update on diagnosis, pathophysiology, and management of diabetic kidney disease

Nephrology, Journal Year: 2021, Volume and Issue: 26(6), P. 491 - 500

Published: Feb. 7, 2021

Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression ESKD some patients. heterogeneous entity terms its clinical manifestations, histopathology rate progression, makes it difficult develop effective therapeutics. It was formerly considered that albuminuria preceded function decline DKD, but recent epidemiological studies revealed distinct group patients presented dysfunction without developing albuminuria. Other comorbidities, such as hypertension, obesity gout, also affect course DKD. The pathophysiology complex multifactorial, involving both metabolic haemodynamic factors. These induce activation intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy epigenetic changes, result inflammation fibrosis. Recently, two groups antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated provide renoprotection on top their glucose-lowering effects. Several other therapeutic agents are being developed evaluated trials.

Language: Английский

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Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 27, 2023

The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. most common form NCD is metabolic diseases, which affect people all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding the will generate novel targets for improved therapies across spectrum. Protein posttranslational modification (PTM) an important term that refers to biochemical specific amino acid residues in target proteins, immensely increases functional diversity proteome. range PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, several PTMs. Here, we offer review roles pathological consequences, including diabetes, obesity, fatty liver hyperlipidemia, atherosclerosis. Building upon this framework, afford description proteins pathways involved by focusing on PTM-based protein modifications, showcase pharmaceutical intervention preclinical studies clinical trials, future perspectives. Fundamental research defining mechanisms whereby regulate open new avenues therapeutic intervention.

Language: Английский

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Oxidative stress and the role of redox signalling in chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 20(2), P. 101 - 119

Published: Oct. 19, 2023

Language: Английский

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Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives

Frontiers in Endocrinology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 2, 2023

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause end-stage renal (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized role tubular injury in pathogenesis Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER inflammation, EMT programmed cell death, been shown to induce contribute progression Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence mineralocorticoid receptor antagonists, stem therapies demonstrated their potential alleviate This review will provide insights into latest mechanisms treatments

Language: Английский

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Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3086 - 3086

Published: March 7, 2024

Diabetic kidney disease (DKD) is a major cause of chronic (CKD), and it heightens the risk cardiovascular incidents. The pathogenesis DKD thought to involve hemodynamic, inflammatory, metabolic factors that converge on fibrotic pathway. Genetic predisposition unhealthy lifestyle practices both play significant role in development progression DKD. In spite recent emergence angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, nonsteroidal mineralocorticoid antagonists (NS-MRAs), current therapies still fail effectively arrest Glucagon-like peptide 1 receptor agonists (GLP-1RAs), promising class agents, possess potential act as renal protectors, slowing Other including pentoxifylline (PTF), selonsertib, baricitinib hold great promise for due their anti-inflammatory antifibrotic properties. Multidisciplinary treatment, encompassing modifications drug therapy, can decelerate Based treatment heart failure, recommended use multiple drugs combination rather than single-use Unearthing mechanisms underlying urgent optimize management Inflammatory (including IL-1, MCP-1, MMP-9, CTGF, TNF-a TGF-β1), along with lncRNAs, not only serve diagnostic biomarkers, but also therapeutic targets. this review, we delve into We explore additional value combing these develop novel strategies. Drawing from understanding pathogenesis, propose HIF AGE epigenetic targets future.

Language: Английский

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Pathophysiologic mechanisms in diabetic kidney disease: A focus on current and future therapeutic targets

Diabetes Obesity and Metabolism, Journal Year: 2020, Volume and Issue: 22(S1), P. 16 - 31

Published: April 1, 2020

Abstract Diabetic kidney disease (DKD) is the primary cause of chronic around globe and one main complications in patients with type 1 2 diabetes. The standard treatment for DKD drugs controlling hyperglycemia high blood pressure. Renin angiotensin aldosterone system blockade sodium glucose cotransporter (SGLT2) inhibition have yielded promising results DKD, but many diabetic on such treatments nevertheless continue to develop leading failure cardiovascular comorbidities. New therapeutic options are urgently required. We review here avenues based insights into mechanisms that recently emerged, including mineralocorticoid receptor antagonists, SGLT2 inhibitors, glucagon‐like peptide‐1 agonist, endothelin A inhibition, anti‐inflammatory agents, autophagy activators epigenetic remodelling. involvement several molecular pathogenesis, together genetic variability this condition, makes it difficult target heterogeneous patient population a single drug. Personalized medicine, taking account mechanistic variability, may therefore improve renal protection DKD.

Language: Английский

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The New Biology of Diabetic Kidney Disease—Mechanisms and Therapeutic Implications

Endocrine Reviews, Journal Year: 2019, Volume and Issue: 41(2), P. 202 - 231

Published: Oct. 21, 2019

Abstract Diabetic kidney disease remains the most common cause of end-stage in world. Despite reductions incidence rates myocardial infarction and stroke people with diabetes over past 3 decades, risk diabetic has remained unchanged, may even be increasing younger individuals afflicted this disease. Accordingly, changes public health policy have to implemented address root causes disease, including rise obesity diabetes, addition use safe effective pharmacological agents prevent cardiorenal complications diabetes. The aim article is review mechanisms pathogenesis therapies that are either clinical practice or emerging development programs for potential treat

Language: Английский

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