Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

Hu, Zejun; Ma, Kun-Ling; Zhang, Yang; Wang, Guihua; Liu, Liang; Lü, Jian; Chen, Peipei; Lü, Chenchen; Liu, Bi‐Cheng

doi:10.1038/aps.2017.177

Cited by 31 publications

(18 citation statements)

References 38 publications

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“…It has been reported that hyperglycaemia‐induced oxidative stress plays an important role in inducing and aggravating inflammatory responses to diabetic kidney injury . Our previous studies demonstrated that reactive oxygen species (ROS) directly damaged some target proteins, aggravating inflammation of renal tissue, and inducing tubulointerstitial injury . Meanwhile, persistent elevated levels of oxidative stress in early diabetic nephropathy may accelerate the progression of nephropathy and even develop end‐stage renal disease (ESRD) .…”

Section: Introductionmentioning

confidence: 99%

“…[1] Our previous studies demonstrated that reactive oxygen species (ROS) directly damaged some target proteins, aggravating inflammation of renal tissue, and inducing tubulointerstitial injury. [2,3] Meanwhile, persistent elevated levels of oxidative stress in early diabetic nephropathy may accelerate the progression of nephropathy and even develop end-stage renal disease (ESRD). [1] However, the mechanisms of cellular oxidative stress in the development of DN are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

Cheng

Chao

Chen

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Oxidative stress plays a critical role in the pathogenesis of diabetic nephropathy (DN). p66shc is closely related to oxidative stress. However, the exact mechanism of its involvement in diabetic nephropathy is poorly understood. This study aimed to investigate the role of the p66shc‐related pathway in diabetic nephropathy. Methods In an in‐vivo experiment, rats were injected with streptozotocin to induce early diabetic nephropathy. The treatment groups were an aminoguanidine group and an enzastaurin group. In an in‐vitro experiment, human renal proximal tubule epithelial cells (HK‐2 cells) were cultured and incubated with high glucose. Key findings Upregulated protein expression of p66shc and p‐p66shc was found in vivo and in vitro when cells were stimulated by high levels of glucose; this effect was accompanied by enhanced oxidative stress and damaged renal function, both of which were alleviated by p66shc siRNA. p66shc regulated NADPH oxidase, further promoting activation of oxidative stress. As an inhibitor of PKCβ, enzastaurin reduced the abnormal expression of p66shc and NADPH oxidase and alleviated renal injury. Conclusions This study demonstrated enzastaurin alleviated diabetic renal injury via modulation of the PKCβ‐p66shc‐NADPH oxidase pathway, which provided a new perspective for the treatment of early DN.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

Cheng

Chao

Chen

et al. 2019

Journal of Pharmacy and Pharmacology

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“…Mounting evidence has demonstrated that the recruitment of immune cells and excessive release of pro-inflammatory cytokines from intrinsic cells play a crucial role in modulating renal fibrosis [3][4][5]. Among the innumerable inflammatory cytokines, interleukin-1β (IL-1β) has been reported to be crucial in inflammation-mediated renal fibrosis in CKD and diabetic nephropathy [6][7][8]. Previous studies have shown that IL-1β expression is remarkably increased in unilateral ureteral obstruction (UUO) mice.…”

Section: Introductionmentioning

confidence: 99%

Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1

Miao

Xie

et al. 2018

Acta Pharmacol Sin

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Caspase-11 is a key upstream modulator for activation of inflammatory response under pathological conditions. In this study, we investigated the roles of caspase-11 in the maturation of interleukin-1β (IL-1β) and development of renal interstitial fibrosis in vivo and in vitro. Mice were subjected to unilateral ureteral obstruction (UUO). The mice were treated with either caspase-11 inhibitor wedelolactone (Wed, 30 mg/kg/day, ig) for 7 days or caspase-11 siRNA (10 nmol/20 g body weight per day, iv) for 14 days. The mice were euthanized on day 14, their renal tissue and blood sample were collected. We found that the obstructed kidney had significantly higher caspase-11 levels and obvious tubular injury and interstitial fibrosis. Treatment with Wed or caspase-11 siRNA significantly mitigated renal fibrosis in UUO mice, evidenced by the improved histological changes. Furthermore, caspase-11 inhibition significantly blunted caspase-1 activation, IL-1β maturation, transforming growth factor-β (TGF-β), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 μmol/L), which stimulated caspase-11 activation and IL-1β maturation. Treatment with IL-1β (20 ng/ml) significantly increased the expression of TGF-β, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-β, fibronectin, and collagen I were suppressed by caspase-11 siRNA or Wed. Finally, we revealed using co-immunoprecipitation that caspase-11 was able to interact with caspase-1 in NRK-52E cells. These results suggest that caspase-11 is involved in UUO-induced renal fibrosis. Elevation of caspase-11 in the obstructed kidney promotes renal fibrosis by stimulating caspase-1 activation and IL-1β maturation.

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“…One of the common manifestations of DN includes the generation of an inflammatory response, which in turn aggravates the progression of DN (28). Uncontrolled diabetes may induce an inflammatory response that is characterized by infiltration of macrophages in the kidneys, causing ECM accumulation, fibrosis and renal malfunction, resulting in proteinuria and ESRD (28)(29)(30). Therefore, it is believed that the development of approaches that can reduce inflammation may be beneficial in the treatment of DN.…”

Section: Discussionmentioning

confidence: 99%

Metformin attenuates diabetic renal injury via the AMPK‑autophagy axis

et al. 2021

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Diabetic nephropathy (DN) is a clinical condition characterized by kidney damage that is observed in patients with diabetes. DN is the main cause of end-stage renal disease (ESRD), which is the final stage of chronic kidney disease. Increasing evidence suggests that metformin, a characteristic oral hypoglycemic drug used for treating diabetes, exerts beneficial effects on various medical conditions and diseases, including cancer, cardiovascular diseases and thyroid-related disorders. However, the impact of metformin on DN remains unknown. The present study investigated whether metformin could attenuate the inflammatory response, fibrosis and increased oxidative stress observed during DN in diabetic/dyslipidemic (db/db) mice. The kidneys of the mice (12-16 weeks) were isolated for immunohistochemistry and western blotting. The results demonstrated that metformin significantly reduced the oxidative damage and fibrosis in the kidneys of db/db mice. Furthermore, metformin treatment significantly inhibited the generation of inflammatory cytokines, including TNF-α and IL-1β in db/db mice. These effects were induced by the activation of the AMP-activated protein kinase (AMPK) pathway, which was mediated by increased phosphorylation of AMPK and mammalian target of rapamycin (mTOR), resulting in autophagy and the simultaneous decrease in reactive oxygen species production, cell apoptosis and inflammatory response. These findings suggested that metformin may reduce DN damage via regulation of the AMPK-mTOR-autophagy axis and indicated that metformin may be considered as a potential target in the treatment of DN.

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Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy

Cited by 31 publications

References 38 publications

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

The PKCβ-p66shc-NADPH oxidase pathway plays a crucial role in diabetic nephropathy

Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1

Metformin attenuates diabetic renal injury via the AMPK‑autophagy axis

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