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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Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 17, 2024

Language: Английский

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Renal Mitochondrial ATP Transporter Ablation Ameliorates Obesity-Induced CKD

Journal of the American Society of Nephrology, Journal Year: 2024, Volume and Issue: 35(3), P. 281 - 298

Published: Jan. 11, 2024

Significance Statement This study sheds light on the central role of adenine nucleotide translocase 2 (ANT2) in pathogenesis obesity-induced CKD. Our data demonstrate that ANT2 depletion renal proximal tubule cells (RPTCs) leads to a shift their primary metabolic program from fatty acid oxidation aerobic glycolysis, resulting mitochondrial protection, cellular survival, and preservation function. These findings provide new insights into underlying mechanisms CKD have potential be translated toward development targeted therapeutic strategies for this debilitating condition. Background The impairment ATP production transport RPTCs has been linked condition is characterized by kidney dysfunction, inflammation, lipotoxicity, fibrosis. In study, we investigated ANT2, which serves as regulator content RPTCs, Methods We generated RPTC-specific knockout ( RPTC-ANT2 −/− ) mice, were then subjected 24-week high-fat diet–feeding regimen. conducted comprehensive assessment morphology, function, alterations these mice. addition, used large-scale transcriptomics, proteomics, metabolomics analyses gain regulating RPTC physiology, overall health. Results revealed obese mice displayed preserved morphology along with notable absence lipotoxicity Ant2 led fundamental rewiring program. Specifically, shifted oxidizing acids energy source favoring phenomenon mediated testis-selective Ant4. Conclusions propose significant RPTC-Ant2 nullification triggers cascade mechanisms, including enhanced ultimately shed complex pathways contributing suggest targets

Language: Английский

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Oxidative Stress Induced by Lipotoxicity and Renal Hypoxia in Diabetic Kidney Disease and Possible Therapeutic Interventions: Targeting the Lipid Metabolism and Hypoxia

Antioxidants, Journal Year: 2023, Volume and Issue: 12(12), P. 2083 - 2083

Published: Dec. 6, 2023

Oxidative stress, a hallmark pathophysiological feature in diabetic kidney disease (DKD), arises from the intricate interplay between pro-oxidants and anti-oxidants. While hyperglycemia has been well established as key contributor, lipotoxicity emerges significant instigator of oxidative stress. Lipotoxicity encompasses accumulation lipid intermediates, culminating cellular dysfunction cell death. However, mechanisms underlying lipotoxic injury DKD still require further investigation. The role metabolism maintenance viability integrity is paramount importance to maintain proper renal function. Recently, energy metabolism, resulting an imbalance oxygen levels condition, may be primary pathophysiologic pathway driving DKD. Therefore, we aim shed light on pivotal stress related hypoxia initiation progression Multifaceted lipotoxicity, including with mitochondrial dysfunction, endoplasmic reticulum activated by unfolded protein response pathway, pro-inflammation, impaired autophagy, are delineated here. Also, explore potential therapeutic interventions for DKD, targeting lipotoxicity- hypoxia-induced These focus ameliorating molecular pathways within enhancing face overload or subsequent This review highlights significance its intervention

Language: Английский

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Cardiometabolic comorbidities and complications of obesity and chronic kidney disease (CKD)

Journal of Clinical & Translational Endocrinology, Journal Year: 2024, Volume and Issue: 36, P. 100341 - 100341

Published: April 2, 2024

Obesity and chronic kidney disease are two ongoing progressive clinical pandemics of major public health care significance. Because their growing prevalence, indolent course consequent complications both these conditions place significant burden on the delivery system especially in developed countries like United States. Beyond chance coexistence same patient based high prevalence it is now apparent that obesity associated with likely has a direct causal role onset, progression severity disease. The causes underlying pathophysiology this myriad, complicated multi-faceted. In review, continuing theme special edition journal " Cross roads between Endocrinology Nephrology" we review epidemiology related (ORCKD), its various pathophysiology. addition, delve into comorbidities ORCKD particular emphasis cardio metabolic consequences then current body evidence for available strategies modulation as well potential unique weight reduction management improvement risk reduction.

Language: Английский

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The Kidney in Obesity: Current Evidence, Perspectives and Controversies

Current Obesity Reports, Journal Year: 2024, Volume and Issue: 13(4), P. 680 - 702

Published: Aug. 14, 2024

Language: Английский

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Multi-epitopes vaccine design for surface glycoprotein against SARS-CoV-2 using immunoinformatic approach

Heliyon, Journal Year: 2024, Volume and Issue: 10(2), P. e24186 - e24186

Published: Jan. 1, 2024

The recent COVID vaccinations have successfully reduced death and severity but did not stop the transmission of viruses by emerging SARS-CoV-2 strain. There is a need for better long-lasting dynamic vaccines numerous prevailing strains evolving virus, necessitating development broad-spectrum being used to infection reducing spread rate re-infection. spike (S) glycoprotein one proteins expressed commonly in early phases infection. It has been identified as most immunogenic protein SARS-CoV-2.

Language: Английский

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Agomelatine Mitigates Kidney Damage in Obese Insulin-Resistant Rats by Inhibiting Inflammation and Necroptosis via the TNF-α/NF-ĸB/p-RIPK3 Pathway

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1940 - 1940

Published: Feb. 24, 2025

Obesity is a risk factor for chronic kidney disease. The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects experimental models through various mechanisms, including the attenuation ER stress oxidative stress. This study aimed to further explore on renal signaling, necroptosis obese, insulin-resistant rats. was induced rats with high-fat diet 16 weeks, followed by 4 weeks treatment 20 mg kg-1 day-1 AGOM or 10 pioglitazone (PIO). results showed improved after PIO, as reduction fasting plasma glucose, insulin, HOMA-IR. Both treatments restored levels signaling proteins. Moreover, inhibited TNFα, TNFR1, NF-ĸB, COX2, IL1β, which attenuated necroptosis-related proteins RIPK3 MLKL. also prevented DNA fragmentation, detected TUNEL assay. In an obese condition, level tight junction protein claudin-1 (CLDN1) enhanced being treated AGOM. conclusion, novel mechanisms associated involved limiting injury were inhibition TNFα/NF-ĸB/p-RIPK3 pathway inflammation necroptosis. suggested could be effective inhibiting dysfunction cases resistance. These findings open new avenues management dysfunction, implications personalized medicine.

Language: Английский

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Renal tubular S100A7a impairs fatty acid oxidation and exacerbates renal fibrosis via both intracellular and extracellular pathway

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2025, Volume and Issue: 1871(3), P. 167656 - 167656

Published: Jan. 6, 2025

Language: Английский

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Downregulation of KLF9 alleviates tubulointerstitial fibrosis by modulating FABP4‐mediated lipid accumulation

IUBMB Life, Journal Year: 2025, Volume and Issue: 77(3)

Published: March 1, 2025

Tubulointerstitial fibrosis (TIF) is a significant determinant in the pathogenesis of chronic kidney disease (CKD) and commonly concurrent with lipid infiltration renal tubules. Nonetheless, precise regulatory mechanism this phenomenon remains incompletely understood. This research sought to uncover involvement underlying KLF9 accumulation lipids linked TIF. As models, TGF-β1 treated HK-2 cells unilateral ureteral obstruction (UUO) mouse model were utilized. Histopathological analysis tissues evaluated by hematoxylin eosin (HE), periodic acid schiff (PAS), Masson's trichrome staining. The levels protein mRNA quantified through western blot real-time quantitative PCR, respectively, while triglyceride (TG) using TG assay kit Oil Red O staining, respectively. Pearson correlation coefficient was employed assess relationship between accumulation. To elucidate mechanisms KLF9's regulation TIF, luciferase reporter assays, chromatin immunoprecipitation (ChIP), rescue experiments performed. identified increase expression correlating inhibition significantly mitigated triggered Subsequent animal studies corroborated these findings, showing that downregulating level FABP4 considerably higher TIF models both vitro vivo. Mechanistically, bound promoter region positively regulated FABP4. KLF9-FABP4 pathway synthesis promoted accumulation, which turn promotes progression Our study has unveiled driving at transcriptional level, culminating subsequent These findings propose targeting deposition as therapeutic strategy may hold promise for addressing

Language: Английский

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