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DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.

ABSTRACT: 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.

SUBMITTER: Li X

PROVIDER: S-EPMC7501299 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.

Li Xiaozhou X Pan Jian J Li Huiling H Li Guangdi G Liu Xiangfeng X Liu Bohao B He Zhibiao Z Peng Zhengyu Z Zhang Hongliang H Li Yijian Y Xiang Xudong X Chai Xiangping X Yuan Yunchang Y Zheng Peilin P Liu Feng F Zhang Dongshan D

Nature communications 20200918 1

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 ...[more]

PMID: 32948751

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Project description:Rationale: Renal fibrosis is commonly recognized as the ultimate pathway for most chronic kidney diseases (CKD). Renal tubular epithelial inflammation drives the initiation and progression of renal fibrosis. Follistatin-like 1 (FSTL1) is a small matricellular protein, whose expression pattern, function and underlying mechanism in regulating renal inflammation and fibrosis remains largely unknown. Methods: We utilized two Fstl1-deficient genetic mouse models: heterozygous Fstl1+/- mice and whole-body Fstl1 conditional knockout mice, and a mouse model with FSTL1 overexpression via adenoviral vector infection. These mice were subjected to unilateral ureteral obstruction (UUO). We used an Fstl1 lineage tracing mouse to investigate the expression and location of induced FSTL1 in the obstructed kidney. We investigated the effect of FSTL1 on TNF-α induced epithelial inflammation and the NF-κB pathway by overexpression or knockdown of FSTL1 in human kidney epithelial cells (HK2). Results: We observed increased expression of FSTL1 in kidneys from patients with CKD, and UUO mouse model of renal injury and fibrosis. Deletion of Fstl1 in mice aggravated UUO-induced inflammatory kidney injury and subsequent fibrosis. Conversely, overexpression of FSTL1 by adenoviral vector infection in mice mitigated expression of proinflammatory cytokines and the fibrotic phenotype. Mechanistically, we identified that increased FSTL1 was mostly derived from the tubular epithelium of the obstructed mouse kidney. FSTL1 inhibited human renal epithelial cell inflammatory responses, as assessed by reducing the NF-κB pathway, release of IL-1β and IL-6, expression of intercellular adhesion molecule 1 (ICAM-1), and monocyte adhesion to kidney epithelial cells. Conclusions: These findings suggest that FSTL1 plays a protective role against kidney fibrosis by inhibiting renal epithelial inflammation via the NF-κB pathway in epithelium, thereby offering a potential novel strategy for treating progressive CKD.

Project description:Acute kidney injury and chronic renal fibrosis are intractable pathological processes to resolve, yet limited strategies are able to effectively address them. Cardamonin (CAD) is a flavonoid with talented antioxidant, anti-inflammatory capacity, and satisfactory biosafety. In our study, animal and cellular models of renal ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) were successfully constructed to confirm whether CAD confers protective effects and underlying mechanisms. Animal experiments demonstrated that CAD application (100 mg/kg) distinctly ameliorated tissue damage and improved renal function. Meanwhile, the continuous oral administration of CAD after UUO surgery efficiently inhibited renal fibrosis as confirmed by hematoxylin-eosin (H&E), Sirius red, and Masson staining as well as the downregulated mRNA and protein expression of collagen I, α-smooth muscle actin (α-SMA), collagen III, and fibronectin. Interestingly, in transforming growth factor β1 (TGF-β1)-stimulated and hypoxia/reoxygenation (H/R)-exposed human kidney-2 (HK-2) cells, protective effects of CAD were again authenticated. Meanwhile, we performed bioinformatics analysis and constructed the "ingredient-target-pathway-disease" network to conclude that the potential mechanisms of CAD protection may be through the regulation of oxidative stress, inflammation, apoptosis, and mitogen-activated protein kinase (MAPK) pathway. Furthermore, experimental data validated that CAD evidently decreased the reactive oxygen species (ROS) production and malondialdehyde (MDA) content while depressing the mRNA and protein expression of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and Il-1β) and inhibiting apoptosis as evidenced by decreased levels of P53, BAX, cleaved caspase-3, and apoptotic rate in renal I/R and UUO models. In addition, the impact of CAD on restraining oxidative stress and inflammation was attributed to its ability to elevate antioxidant enzyme activities including catalase, superoxide dismutase 1 (SOD1), and superoxide dismutase 2 (SOD2) and to inhibit the inflammation-associated MARK/nuclear factor-κB (MAPK/NF-κB) signaling pathway. In conclusion, cardamonin restored the antioxidative capacity to block oxidative stress and suppressed the MAPK/NF-κB signaling pathway to alleviate inflammatory response, thus mitigating I/R-generated acute kidney injury/UUO-induced renal fibrosis in vivo and in vitro, which indicated the potential therapeutic advantage of cardamonin in attenuating acute and chronic kidney injuries.

Dataset Information

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.

Publications

DsbA-L mediated renal tubulointerstitial fibrosis in UUO mice.

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