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Published on: May 10, 2024
SIRT5 induces tubulointerstitial fibrosis via GLS1 in diabetic nephropathy
Zhi Xu1, Xinhao Li1, Zhichen Cai1
1Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
Abstract:
Tubulointerstitial fibrosis composed of epithelial-mesenchymal transition (EMT) and the resulting extracellular matrix (ECM) accumulation is the primary feature of diabetic nephropathy (DN), but its mechanism remained unclear. In the present study, sirtuin 5 (SIRT5) was screened for the key pathogenic factor by proteomics analysis in DN mice. Then SIRT5 was overexpressed and knocked down in the kidney of mice and in renal tubular epithelial cells. It was found that the elevation of SIRT5 in renal tubular epithelial cells exacerbated EMT, ECM accumulation and worsened the renal function of mice. Using real-time PCR, co-immunoprecipitation, and cycloheximide tracking assay, we found that SIRT5 increased the desuccinylation, the ubiquitination of kidney type glutaminase (GLS1), which thereby caused an increase in GLS1 protein. Meanwhile, when GLS1 protein maintained at some level, changes in SIRT5 do not impact the EMT process and the subsequent ECM accumulation. Furthermore, we found that SIRT5 was increased in kidneys of DN patients, it was also up-regulated in the urine of DN patients and had correlations with renal function of patients. Collectively, SIRT5 induces tubulointerstitial fibrosis via GLS1 in DN, which renders it a promising therapeutic target for DN.
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