Molecular mechanism of renal lipid accumulation in diabetic kidney disease DOI Creative Commons

Zhengying Fang,

Ruijie Liu, Jingyuan Xie

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(11)

Published: June 1, 2024

Abstract Diabetic kidney disease (DKD) is a leading cause of end stage renal with unmet clinical demands for treatment. Lipids are essential cell survival; however, cells have limited capability to metabolize overloaded lipids. Dyslipidaemia common in DKD patients and ectopic lipid accumulation associated progression. Unveiling the molecular mechanism involved regulation crucial exploring potential therapeutic targets. In this review, we focused on underlying cholesterol, oxysterol fatty acid metabolism disorder context DKD. Specific regulators different compartment TREM2 macrophages, lipid‐related macrophages DKD, were discussed. The role sodium‐glucose transporter 2 inhibitors improving was summarized.

Language: Английский

Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions DOI Creative Commons
Rajesh Kumar Jha,

Sara Lopez-Trevino,

Haritha R. Kankanamalage

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1098 - 1098

Published: May 15, 2024

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

Language: Английский

Citations

21
Metabolism at the crossroads of inflammation and fibrosis in chronic kidney disease DOI
Verónica Miguel, Isaac Shaw, Rafael Kramann

et al.

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

Published: Sept. 17, 2024

Language: Английский

Citations

19
HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation DOI Creative Commons

Guangyan Yang,

Chuanrui Ma,

Yuanli Chen

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(3), P. 115339 - 115339

Published: Feb. 19, 2025

Language: Английский

Citations

2
Tubular Mitochondrial Dysfunction, Oxidative Stress, and Progression of Chronic Kidney Disease DOI Creative Commons
Miguel Fontecha‐Barriuso,

Ana M. López-Diaz,

Juan Guerrero‐Mauvecin

et al.

Antioxidants, Journal Year: 2022, Volume and Issue: 11(7), P. 1356 - 1356

Published: July 12, 2022

Acute kidney injury (AKI) and chronic disease (CKD) are interconnected conditions, CKD is projected to become the fifth leading global cause of death by 2040. New therapeutic approaches needed. Mitochondrial dysfunction oxidative stress have emerged as drivers in acute settings, promoting AKI-to-CKD transition. In this work, we review role mitochondrial AKI progression discuss novel approaches. Specifically, evidence for diverse models (nephrotoxicity, cytokine storm, ischemia-reperfusion injury) (diabetic disease, glomerulopathies) discussed; clinical implications information on key mitochondria-related transcriptional regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha, transcription factor EB (PGC-1α, TFEB), carnitine palmitoyl-transferase 1A (CPT1A) addressed; current status development targeting mitochondria updated; barriers mitochondria-targeted interventions discussed, including lack diagnostic tests that allow us categorize baseline renal dysfunction/mitochondrial monitor its response intervention. Finally, milestones further research proposed.

Language: Английский

Citations

64
PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum–Mitochondria Contact and Mitophagy in Diabetic Nephropathy DOI Open Access
Chenrui Li, Li Li, Ming Yang

et al.

Diabetes, Journal Year: 2022, Volume and Issue: 71(5), P. 1034 - 1050

Published: Feb. 8, 2022

Mitochondria-associated endoplasmic reticulum membrane (MAM) may have a role in tubular injury diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), critical regulator MAM formation, is significantly decreased renal tubules patients with DN, and PACS-2 positively correlated function negatively degrees tubulointerstitial lesions. Conditional deletion Pacs-2 proximal (PTs) aggravates albuminuria streptozotocin-induced mouse model diabetes. Mitochondrial fragmentation, disruption, defective mitophagy accompanied by altered mitochondrial dynamics mitophagic proteins, including Drp1 Becn1, are observed mice; these changes more pronounced PT-specific knockout mice. In vitro, overexpression HK-2 cells alleviates excessive fission induced high glucose concentrations through blocking recruitment DRP1 subsequently restores integrity enhances mitophagy. Mechanistically, binds to BECN1 mediates relocalization MAM, where it promotes formation mitophagosome. Together, data highlight an important previously unrecognized ameliorating DN facilitating

Language: Английский

Citations

51
Cellular senescence of renal tubular epithelial cells in renal fibrosis DOI Creative Commons
Junqing Zhang, Yingying Li, Xueyan Zhang

et al.

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

Published: Feb. 28, 2023

Renal fibrosis (RF) is the common pathological manifestation of virtually all chronic kidney diseases (CKD) and one major causes end-stage renal disease (ESRD), but pathogenesis which still unclear. tubulointerstitial lesions have been identified as a key hallmark RF pathology. tubular epithelial cells are resident tubulointerstitium play an important role in recovery versus following injury. Studies recent years shown that senescence can accelerate progression fibrosis. Oxidative stress(OS), telomere attrition DNA damage cell senescence. Current interventions therapeutic strategies for cellular include calorie restriction routine exercise, Klotho, senolytics, senostatics, other related drugs. This paper provides overview mechanisms signaling pathways including Wnt/β-catenin/RAS, Nrf2/ARE STAT-3/NF-κB pathway involved therapies targeting future potential patients. These findings may offer promise further treatment CKD.

Language: Английский

Citations

42
Dapagliflozin Ameliorates Renal Tubular Ferroptosis in Diabetes via SLC40A1 Stabilization DOI Creative Commons
Bin Huang, Wenjie Wen, Shandong Ye

et al.

Oxidative Medicine and Cellular Longevity, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 17

Published: Aug. 10, 2022

Tubular injury has been shown to play a critical role in the morbidity of diabetic kidney disease (DKD); ferroptosis often occurs tubules during renal development. This study was aimed at evaluating inhibitory effects and potential mechanism dapagliflozin (DAPA) against diabetic-related kidney. C57BL/6 mice were fed high-fat diet (HFD) for 12 weeks, administered small dose streptozocin (STZ) three consecutive days by intraperitoneal injection, then orally (10 mg/kg/day) 8 weeks. Mouse blood urine samples collected, their cortices harvested subsequent investigations. The DAPA also evaluated HK-2 cells subjected simulated conditions through excess glucose or palmitic acid (PA) administration. significantly ameliorated tubular independently glycemic control model mice. In vivo vitro investigations showed that inhibiting ferroptosis. Docking experiments demonstrated SLC40A1 could bind with each other may consequently reduce ubiquitination degradation. conclusion, this study, protective DAPA, irrespective control, observed mouse model. via stabilization, be underlying its action. To best our knowledge, is first investigate treatment DKD.

Language: Английский

Citations

41
SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease DOI Creative Commons

Yong-Ping Lu,

Zeyu Zhang, Hongwei Wu

et al.

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: Sept. 14, 2022

Abstract Diabetic kidney disease (DKD) is the leading cause of end-stage renal (ESRD) worldwide. SGLT2 inhibitors are clinically effective in halting DKD progression. However, underlying mechanisms remain unclear. The serum and kidneys mice with were analyzed using liquid chromatography tandem mass spectrometry (LC–MS/MS)-based metabolomic proteomic analyses. Three groups established: placebo-treated littermate db/m mice, db/db EMPA-treated mice. Empagliflozin (EMPA) placebo (10 mg/kg/d) administered for 12 weeks. EMPA treatment decreased Cys-C urinary albumin excretion compared by 78.60% 57.12%, respectively (p < 0.001 all cases). Renal glomerular area, interstitial fibrosis glomerulosclerosis 16.47%, 68.50% 62.82%, 0.05 Multi-omic analysis revealed that altered protein metabolic profiles group, including 32 proteins, 51 94 metabolites 37 metabolites. Five EMPA-related pathways identified integrating analyses, which involved purine metabolism; pyrimidine tryptophan nicotinate nicotinamide metabolism, glycine, serine threonine metabolism serum. In conclusion, this study demonstrated reprogramming DKD. improved function morphology regulating reprogramming, regulation reductive stress, alleviation mitochondrial dysfunction reduction oxidative stress reaction.

Language: Английский

Citations

41
A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury DOI Creative Commons
Chen Yang,

Huidie Xu,

Dong Yang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 17, 2023

Abstract Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, acts as a biomarker for various diseases. However, the exact role underlying mechanism of KIM1 progression AKI remain elusive. Herein, we report that tubular specific knockout Kim1 attenuates cisplatin- or ischemia/reperfusion-induced male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which downregulated AKI, binds to promoter represses its expression. Injury-induced ECD domain death receptor 5 (DR5), activates DR5 following caspase cascade by promoting multimerization, thus induces cell apoptosis exacerbates AKI. Blocking KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against Here, reveal YY1-KIM1-DR5 axis warrants future exploration therapeutic targets.

Language: Английский

Citations

30
Sensing Dying Cells in Health and Disease DOI Creative Commons

Elena Tutunea-Fatan,

Shabitha Arumugarajah,

Rita S. Suri

et al.

Journal of the American Society of Nephrology, Journal Year: 2024, Volume and Issue: 35(6), P. 795 - 808

Published: Feb. 14, 2024

Kidney injury molecule-1 (KIM-1), also known as T-cell Ig and mucin domain-1 (TIM-1), is a widely recognized biomarker for AKI, but its biological function less appreciated. KIM-1/TIM-1 belongs to the domain family of conserved transmembrane proteins, which bear characteristic six-cysteine Ig-like variable domain. The latter enables binding natural ligand, phosphatidylserine, expressed on surface apoptotic cells necrotic cells. in variety tissues plays fundamental roles regulating sterile inflammation adaptive immune responses. In kidney, KIM-1 upregulated injured renal proximal tubule cells, transforms them into phagocytes clearance dying helps dampen inflammation. TIM-1, T B killer essential cell activation regulatory functions host. Functional polymorphisms gene KIM-1/TIM-1, HAVCR1 , have been associated with susceptibility immunoinflammatory conditions hepatitis A virus-induced liver failure, thought be due differential ability variants bind phosphatidylserine. This review will summarize role health disease potential clinical applications therapeutic target humans.

Language: Английский

Citations

14