Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy

Chen, Xianghui; Han, Yachun; Gao, Peng; Yang, Ming; Xiao, Li; Xiong, Xiaofen; Zhao, Hao; Tang, Chengyuan; Chen, Guochun; Zhu, Xuejing; Yuan, Shuguang; Liu, Fuyou; Dong, Lily Q.; Liu, Feng; Kanwar, Yashpal S.; Sun, Lin

doi:10.1016/j.kint.2018.10.038

Cited by 58 publications

(66 citation statements)

References 50 publications

(73 reference statements)

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“…Urine N‐acetyl‐β‐ d glucosaminidase (NAG) was assessed using an automated colorimetric method (Pacific). Urinary creatinine and albumin were measured with a creatinine assay kit and an Albuwell M kit (Exocell) 24 …”

Section: Methodsmentioning

confidence: 99%

HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

et al. 2020

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Objectives In diabetic nephropathy (DN), hypoxia‐inducible factor‐1α (HIF‐1α) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF‐1α, such as haem oxygenase‐1 (HO‐1), but the exact mechanisms are incompletely understood. Materials and methods Mice with proximal tubule‐specific knockout of HIF‐1α (PT‐HIF‐1α−/− mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl2) was applied to HK‐2 cells. Results Our study first verified that conditional knockout of HIF‐1α worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT‐HIF‐1α−/− mice. In vitro study showed that compared to control group, HK‐2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF‐1α or treatment with a HO‐1 agonist. Importantly, cotreatment with a HIF‐1α inhibitor and a HO‐1 agonist rescued the HK‐2 cells from the negative impacts of the HIF‐1α inhibitor. Conclusions These data revealed that HIF‐1α exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO‐1 upregulation.

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Section: Methodsmentioning

confidence: 99%

HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

et al. 2020

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“…To our knowledge, we are the first to have found that tubular DsbA-L mediated UUO-induced TIF, renal cell apoptosis, and inflammation in mice. It is completely opposite to the role of DsbA-L in DN 17,18 ; the possible reason is that the difference between the role of system and tubular KO DsbA-L in DN and UUO model. In addition, we also found that DsbA-L mediated I/R, low-dose cisplatin, and aristolochic acid-induced TIF.…”

Section: Discussionmentioning

confidence: 85%

“…Previous studies have demonstrated that overexpression of DsbA-L has a renal-protective role against lipid-related kidney damage in DN 17 . In the current study, we initially induced DsbA-L in TGF-β1-treated BUMPT cells as well as in the kidneys of UUO mice and Ob patients, especially as the mitochondrion damage existed in the UUO model 27,28 ; we presumed that the expression of DsbA-L in kidney tubular injury was associated with the damage of mitochondrion damage (see Fig.…”

Section: Discussionmentioning

confidence: 97%

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DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Pan

et al. 2020

Nat Commun

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Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.

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“…Next, we sought to knockdown Smad4 in type 2 diabetes with established kidney disease. In this model, hypertensive eNOS À/À mice on the C57BL/ 6J background are placed on a high fat diet (HFD) for 30 weeks with a single STZ injection on week 8 to further increase blood glucose levels to diabetic state while remaining hyperinsulinaemia, a characteristic of type 2 diabetes [19][20][21][22][23][24][25][26][27][28][29][30][31]. This regimen results in hyperglycaemia, hyperinsulinaemia, albuminuria, glomerulosclerosis and reduced kidney function ( Fig EV1).…”

Section: Resultsmentioning

confidence: 99%

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

Sun

Chen

et al. 2020

EMBO Reports

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Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. TGF-b1/Smad3 signalling plays a major pathological role in DN; however, the contribution of Smad4 has not been examined. Smad4 depletion in the kidney using anti-Smad4 locked nucleic acid halted progressive podocyte damage and glomerulosclerosis in mouse type 2 DN, suggesting a pathogenic role of Smad4 in podocytes. Smad4 is upregulated in human and mouse podocytes during DN. Conditional Smad4 deletion in podocytes protects mice from type 2 DN, independent of obesity. Mechanistically, hyperglycaemia induces Smad4 localization to mitochondria in podocytes, resulting in reduced glycolysis and oxidative phosphorylation and increased production of reactive oxygen species. This operates, in part, via direct binding of Smad4 to the glycolytic enzyme PKM2 and reducing the active tetrameric form of PKM2. In addition, Smad4 interacts with ATPIF1, causing a reduction in ATPIF1 degradation. In conclusion, we have discovered a mitochondrial mechanism by which Smad4 causes diabetic podocyte injury.

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Disulfide-bond A oxidoreductase-like protein protects against ectopic fat deposition and lipid-related kidney damage in diabetic nephropathy

Cited by 58 publications

References 50 publications

HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice

Smad4 promotes diabetic nephropathy by modulating glycolysis and OXPHOS

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