Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115670 - 115670

Published: Oct. 13, 2023

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as major contributor to end-stage renal disease. The glomerular filtration barrier, composed podocytes, endothelial cells, the basement membrane, plays vital role maintaining function. Disruptions podocyte function, including hypertrophy, shedding, reduced density, apoptosis, can impair integrity resulting elevated proteinuria, abnormal rate, increased creatinine levels. Hence, recent research increasingly focused on injury DN, with growing emphasis exploring therapeutic interventions targeting injury. Studies have revealed that factors such lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, impaired autophagy contribute This review aims summarize underlying mechanisms DN provide an overview current status regarding experimental drugs DN. findings presented herein may offer potential targets strategies for management associated

Language: Английский

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Protective effect of compound K against podocyte injury in chronic kidney disease by maintaining mitochondrial homeostasis

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 2, 2025

Chronic kidney disease (CKD) stands as a formidable global health challenge, often advancing to end-stage renal (ESRD) with devastating morbidity and mortality. At the central of this progression lies podocyte injury, critical determinant glomerular dysfunction. Compound K (CK), bioactive metabolite derived from ginsenoside, has emerged compelling candidate for nephroprotective therapy. Here, we unveil profound therapeutic potential CK in folic acid (FA)-induced CKD mouse model, demonstrating its ability restore function mitigate injury. exerted effects by reinforcing inter-podocyte junctions, suppressing aberrant motility, preventing detachment apoptosis, thereby safeguarding filtration barrier. Mechanistically, identified mitochondrial dysregulation key driver excessive oxidative stress, which is commonly associated damage. remarkably restored homeostasis attenuating pathological fission enhancing mitophagy, rebalancing delicate network. Intriguingly, may disrupt formation Drp1-Bax dimer, crucial mediator further averting loss. Collectively, our findings highlight potent agent, offering novel avenue management redefining possibilities battle against progressive disease.

Language: Английский

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Astragaloside IV attenuates podocyte apoptosis through ameliorating mitochondrial dysfunction by up-regulated Nrf2-ARE/TFAM signaling in diabetic kidney disease

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 203, P. 45 - 57

Published: April 6, 2023

Defective antioxidant system as well mitochondrial dysfunction contributes to the pathogenesis and progression of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related 2 (Nrf2)-mediated signaling is central defensive mechanism against oxidative stress therefore pharmacological activation Nrf2 a promising therapeutic strategy. In this study, using molecular docking we found that Astragaloside IV (AS-IV), an active ingredient from traditional formula Huangqi decoction (HQD), exerted higher potential promote escape Keap1-Nrf2 interaction via competitively bind amino acid sites in Keap1. When podocyte exposed high glucose (HG) stimulation, morphological alterations apoptosis were presented accompanied by transcription A (TFAM) downregulation. Mechanistically, HG promoted decrease mitochondria-specific electron transport chain (ETC) complexes, ATP synthesis mtDNA content increased ROS production. Conversely, all these defects dramatically alleviated AS-IV, but suppression with inhibitor or siRNA TFAM simultaneously AS-IV efficacy. Moreover, experimental mice exhibited significant renal injury disorder, corresponding decreased expression TFAM. On contrary, reversed abnormality also restored. Taken together, present findings demonstrate improvement on function, thereby resistance stress-induced apoptosis, process closely associated Nrf2-ARE/TFAM signaling.

Language: Английский

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Triptolide protects against podocyte injury in diabetic nephropathy by activating the Nrf2/HO-1 pathway and inhibiting the NLRP3 inflammasome pathway

Renal Failure, Journal Year: 2023, Volume and Issue: 45(1)

Published: March 20, 2023

Objectives: Diabetic nephropathy (DN) is the most common microvascular complication of diabetes mellitus. This study investigated mechanism triptolide (TP) in podocyte injury DN.Methods: DN mouse models were established by feeding with a high-fat diet and injecting streptozocin MPC5 induced high-glucose (HG), followed TP treatment. Fasting blood glucose renal function indicators, such as 24 h urine albumin (UAlb), serum creatinine (SCr), urea nitrogen (BUN), kidney/body weight ratio mice examined. H&E TUNEL staining performed for evaluating pathological changes apoptosis tissue. The markers, reactive oxygen species (ROS), oxidative stress (OS), inflammatory cytokines, nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway-related proteins, pyroptosis detected Western blotting corresponding kits. cell viability evaluated MTT Hoechst 33342/PI double-fluorescence staining. Nrf2 inhibitor ML385 was used to verify regulation on Nrf2.Results: improved histopathological mice, alleviated podocytes injury, reduced OS ROS activating Nrf2/heme oxygenase-1 (HO-1) pathway, weakened inhibiting nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome pathway. In vitro experiments further verified inhibition mediating Nrf2/HO-1 NLRP3 pathways. Inhibition reversed protective effect cells.Conclusions: Overall, via Nrf2/ROS/NLRP3 axis.

Language: Английский

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Research progress on multiple cell death pathways of podocytes in diabetic kidney disease

Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(1)

Published: Oct. 12, 2023

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, failure. The injury death podocytes keys to DKD. Currently, a variety cell modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. signaling pathways leading these processes interconnected can be activated simultaneously or parallel. They essential for survival that determine fate cells. With deepening research on mechanism death, more researchers devoted their attention underlying pathologic drug therapy In this paper, we discussed podocyte physiologic role DKD processes. We also provide an overview types specific mechanisms involved each type DKD, as well related targeted methods drugs reviewed. last part discuss complexity potential crosstalk between various which will help improve understanding lay foundation new ideal strategies treatment future.

Language: Английский

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(Pro)renin receptor mediates tubular epithelial cell pyroptosis in diabetic kidney disease via DPP4-JNK pathway

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 5, 2024

Abstract Background (Pro)renin receptor (PRR) is highly expressed in renal tubules, which involved physiological and pathological processes. However, the role of PRR, tubular epithelial cells, diabetic kidney disease (DKD) remain largely unknown. Methods In this study, biopsies, urine samples, public RNA-seq data from DKD patients were used to assess PRR expression cell pyroptosis cells. The regulation by was investigated situ injection adeno-associated virus9 (AAV9)-shRNA into db/db mice, knockdown or overexpression HK-2 To reveal underlined mechanism, interaction with potential binding proteins explored using BioGrid database. Furthermore, direct dipeptidyl peptidase 4 (DPP4), a pleiotropic serine increases blood glucose degrading incretins under conditions, confirmed co-immunoprecipitation assay immunostaining. Results Higher found tubules positively correlated injuries patients, parallel cells pyroptosis. Knockdown kidneys significantly blunted mice injury alleviating resultant interstitial inflammation. Moreover, silencing blocked high glucose-induced pyroptosis, whereas enhanced pyroptotic death Mechanistically, selectively bound cysteine-enrich region C-terminal DPP4 augmented protein abundance DPP4, leading downstream activation JNK signaling suppression SIRT3 FGFR1 signaling, then subsequently mediated death. Conclusions This study identified significant pathogenesis DKD; specifically, promoted via highlighting that could be promising therapeutic target DKD.

Language: Английский

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FTO‐mediated m6A modification of serum amyloid A2 mRNA promotes podocyte injury and inflammation by activating the NF‐κB signaling pathway

The FASEB Journal, Journal Year: 2024, Volume and Issue: 38(2)

Published: Jan. 9, 2024

Abstract Diabetic kidney disease (DKD) is one of the severe complications diabetes mellitus, yet there no effective treatment. Exploring development DKD essential to Podocyte injury and inflammation are closely related DKD. However, mechanism podocyte progression in remains largely unclear. Here, we observed that FTO expression was significantly upregulated high glucose‐induced podocytes overexpression promoted inflammation. By performing RNA‐seq MeRIP‐seq with control or without knockdown, revealed serum amyloid A2 (SAA2) a target FTO‐mediated m6A modification. Knockdown markedly increased SAA2 mRNA modification decreased expression. Mechanistically, demonstrated might participate through activation NF‐κB signaling pathway. Furthermore, by generating podocyte‐specific adeno‐associated virus 9 (AAV9) knockdown mice, discovered depletion restored Together, our results suggested upregulation m6A‐dependent regulation, thus suggesting may be therapeutic for diabetic disease.

Language: Английский

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Mechanisms and implications of podocyte autophagy in chronic kidney disease

AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 326(6), P. F877 - F893

Published: April 11, 2024

Autophagy is a protective mechanism through which cells degrade and recycle proteins organelles to maintain cellular homeostasis integrity. An accumulating body of evidence underscores the significant impact dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide comprehensive overview diverse types their regulation homeostasis, with specific emphasis podocytes. Furthermore, discuss recent findings that focus functional role different during disease. The intricate interplay between health requires further research, critical for understanding pathogenesis CKD developing targeted therapeutic interventions.

Language: Английский

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Poricoic acid A induces mitophagy to ameliorate podocyte injury in diabetic kidney disease via downregulating FUNDC1

Journal of Biochemical and Molecular Toxicology, Journal Year: 2023, Volume and Issue: 37(12)

Published: Sept. 14, 2023

Diabetic kidney disease (DKD) is a devastating complication of diabetes mellitus (DM) and the most prevalent chronic (CKD). Poricoic acid A (PAA), component isolated from Traditional Chinese Medicine (TCM) Poria cocos, has hypoglycaemic anti-fibrosis effects. However, role PAA in DKD remains largely unclear. To mimics an vitro model DKD, mouse podocyte MPC5 cells were treated with high glucose (25 mM; HG) for 24 h. CCK-8 flow cytometry assays conducted assessing cell viability apoptosis. Meanwhile, streptozotocin (STZ) was used to induce experimental mice by intraperitoneal injection. notably inhibited apoptosis inflammation, reduced generation ROS, elevated MMP level HG-treated cells. Moreover, obviously blood urine protein levels, renal fibrosis mice. markedly increased LC3 ATG5 levels declined p62 FUNDC1 tissues mice, leading activation mitophagy. Furthermore, downregulation also apoptosis, promoted mitophagy As expected, knockdown further enhanced protective following HG treatment, indicating that induction could attenuate injury. Collectively, exert beneficial effects on injury promoting via downregulating FUNDC1. These findings suggested may have great potential alleviating DKD.

Language: Английский

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STING deletion alleviates podocyte injury through suppressing inflammation by targeting NLRP3 in diabetic kidney disease

Cellular Signalling, Journal Year: 2023, Volume and Issue: 109, P. 110777 - 110777

Published: June 16, 2023

Language: Английский

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