VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-Mediated Autophagy Pathway in Diabetic Nephropathy

Wang, Bin; Qian, Jie; Tang, Tao-Tao; Lin, Li-lu; Yu, Nan; Guo, Honglei; Ni, Wei-Jie; Lv, Ling-Li; Wen, Yi; Li, Zuo‐Lin; Wu, Min; Cao, Jun; Liu, Bi‐Cheng

doi:10.2337/db21-0205

Cited by 18 publications

(10 citation statements)

References 40 publications

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“…Autophagy has been shown to be essential to the maintenance of cellular homeostasis in podocytes [26, 27]. Emerging evidence has suggested that dysregulated autophagy may contribute to both glomerular and tubulointerstitial pathologies in the kidneys of DKD [17, 28, 29]. Recent studies have also revealed that vitamin D-vitamin D receptor regulates defective autophagy in renal tubular epithelial cells and podocytes [13, 16].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease

Zhang¹,

Zhang²,

Wen³

et al. 2023

Kidney Blood Press Res

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Introduction: Restoration of podocyte autophagy is considered as a feasible strategy for the treatment of diabetic kidney disease (DKD). This study aimed at investigating the protective effect and potential mechanism of vitamin D on podocyte injury of DKD. Methods: Type 2 diabetic db/db mice received intraperitoneal injections of vitamin D analogue paricalcitol 400ng/kg per day for 16 weeks. Immortalized mouse podocytes were cultured in high glucose (HG) medium with active vitamin D3 calcitriol or autophagy inhibitor 3-methyladeine. Renal function and urine albumin creatinine ratio were assessed at week 24. HE, PAS staining and electron microscopy were used to evaluate renal histopathology and morphological changes. Immunohistochemistry, immunoﬂuorescence and western blot were used to evaluate protein expression of nephrin and podocin in kidney tissue and podocytes. The expression of autophagy- related proteins (LC3, beclin-1, VPS34) and apoptosis-related proteins (cleaved caspase 3, Bax) was determined by western blotting. Podocyte apoptosis was further evaluated by using flow cytometer. Results: Albuminuria in a db/db mouse model was markedly attenuated after treatment with paricalcitol. This was accompanied by alleviation of mesangial matrix expansion and podocyte injury. Besides, the impaired autophagy in podocytes under diabetic conditions was also markedly enhanced after paricalcitol or calcitriol treatment, accompanied by restored decreased podocyte slit diaphragm proteins podocin and nephrin. Furthermore, the protective effect of calcitriol against HG induced podocyte apoptosis could be abated by autophagy inhibitor 3-methyladenine. Conclusion: Vitamin D ameliorates podocyte injury of DKD by enhancing podocyte autophagy activity, which may become a potential candidate autophagy activator for the therapeutic interventions for DKD.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease

Zhang¹,

Zhang²,

Wen³

et al. 2023

Kidney Blood Press Res

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“…Moreover, the expression levels of P53 and miR-214 negatively correlated with the expression levels of ULK1 in those patients (Figure 2) [67]. Interestingly, Wang et al revealed that ineffective autophagic flux prevents P62-dependent degradation of zonula occludens-1 (ZO-1), a tight junction protein, and accelerates slit diaphragm replacement by tight junction in podocytes, causing foot process effacement [72].…”

Section: Sestrin2 Improves Autophagy In Diabetic Nephropathymentioning

confidence: 97%

Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy

Ala

2023

Journal of Diabetes Research

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Sestrin2 regulates cell homeostasis and is an upstream signaling molecule for several signaling pathways. Sestrin2 leads to AMP-activated protein kinase- (AMPK-) and GTPase-activating protein activity toward Rags (GATOR) 1-mediated inhibition of mammalian target of rapamycin complex 1 (mTORC1), thereby enhancing autophagy. Sestrin2 also improves mitochondrial biogenesis via AMPK/Sirt1/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) signaling pathway. Blockade of ribosomal protein synthesis and augmentation of autophagy by Sestrin2 can prevent misfolded protein accumulation and attenuate endoplasmic reticulum (ER) stress. In addition, Sestrin2 enhances P62-mediated autophagic degradation of Keap1 to release nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 release by Sestrin2 vigorously potentiates antioxidant defense in diabetic nephropathy. Impaired autophagy and mitochondrial biogenesis, severe oxidative stress, and ER stress are all deeply involved in the development and progression of diabetic nephropathy. It has been shown that Sestrin2 expression is lower in the kidney of animals and patients with diabetic nephropathy. Sestrin2 knockdown aggravated diabetic nephropathy in animal models. In contrast, upregulation of Sestrin2 enhanced autophagy, mitophagy, and mitochondrial biogenesis and suppressed oxidative stress, ER stress, and apoptosis in diabetic nephropathy. Consistently, overexpression of Sestrin2 ameliorated podocyte injury, mesangial proliferation, proteinuria, and renal fibrosis in animal models of diabetic nephropathy. By suppressing transforming growth factor beta (TGF-β)/Smad and Yes-associated protein (YAP)/transcription enhancer factor 1 (TEF1) signaling pathways in experimental models, Sestrin2 hindered epithelial-mesenchymal transition and extracellular matrix accumulation in diabetic kidneys. Moreover, modulation of the downstream molecules of Sestrin2, for instance, augmentation of AMPK or Nrf2 signaling and inhibition of mTORC1, has been protective in diabetic nephropathy. Regarding the beneficial effects of Sestrin2 on diabetic nephropathy and its interaction with several signaling molecules, it is worth targeting Sestrin2 in diabetic nephropathy.

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“…Given the reciprocal interaction of NLRP3 and autophagy and the role of dysregulated autophagy in the pathogenesis of DKD, we considered that the interaction between Nlrp3 and autophagy factors may be a potential mechanism by which Nlrp3 in podocytes exerts additional effects independent of caspase-1. [34][35][36] To examine whether glomerular autophagy is differentially regulated by Nlrp3 and caspase-1 in diabetic mice, we determined glomerular levels of autophagy markers LC3II/LC3I and p62 (sequestosome 1) in diabetic Nlrp3 V-pod , diabetic Nlrp3 KO-Pod , and diabetic Casp1 KO-Pod glomeruli by immunoblotting. Consistent with other reports, autophagy was impaired in diabetic glomeruli of wild-type mice (Pod-Cre ), as reflected by a decreased LC3II/LC3I ratio and increased p62 levels (Figure 7a-c).…”

Section: Podocyte-specific Nlrp3 Deficiency But Not Caspase-1 Deficie...mentioning

confidence: 99%

Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease

Shahzad

Fatima

Khawaja

et al. 2022

Kidney International

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VDR/Atg3 Axis Regulates Slit Diaphragm to Tight Junction Transition via p62-Mediated Autophagy Pathway in Diabetic Nephropathy

Abstract: Supplemental Figure 1. The average content of ZO-1 experienced an increasing trend in DN patients with the pathological progression from stage IIa to IV. The ratio of IOD of ZO-1 (A) and p62 (B) to WT-1 count in the glomeruli of DN patents at different stages as indicated.

Cited by 18 publications

References 40 publications

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease

Vitamin D Ameliorates Podocyte Injury by Enhancing Autophagy Activity in Diabetic Kidney Disease

Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy

Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease

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