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  2. Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease

Sestrin2 remedies podocyte injury via orchestrating TSP-1/TGF-β1/Smad3 axis in diabetic kidney disease

  • Cell Death Dis. 2022 Jul 30;13(7):663. doi: 10.1038/s41419-022-05120-0.
Shan Song 1 2 3 Chonglin Shi 1 Yawei Bian 1 Zhaohua Yang 1 Lin Mu 1 3 4 Haijiang Wu 1 2 3 Huijun Duan 1 2 3 Yonghong Shi 5 6 7
Affiliations

Affiliations

  • 1 Department of Pathology, Hebei Medical University, Shijiazhuang, China.
  • 2 Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China.
  • 3 Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.
  • 4 The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 5 Department of Pathology, Hebei Medical University, Shijiazhuang, China. yonghongshi@163.com.
  • 6 Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China. yonghongshi@163.com.
  • 7 Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. yonghongshi@163.com.
Abstract

Sestrin2 is identified as a stress-induced protein and could functionate in many aspects. In our study, we investigated the latent impact of Sestrin2 on podocyte injury and its molecular mechanism in vivo and in vitro in diabetic kidney disease (DKD). Sestrin2 was low-expressed in renal biopsies from individuals with DKD, the glomeruli from diabetic mice, and mouse podocytes exposed to high glucose (HG). Sestrin2 overexpression ameliorated HG-induced phenotypic alterations, Apoptosis, and oxidative stress in conditionally immortalized mouse podocytes and modulated the activity of Thrombospondin-1 (TSP-1)/transforming growth factor (TGF-β1)/SMAD3 pathway in podocytes. Moreover, TSP-1 inhibitor LSKL or TGF-β blocker Pirfenidone arrested podocyte injury induced by HG. Streptozotocin (STZ) was employed to render equivalent diabetes in B6-TgN (CMV-Sestrin2) (TgN) and wild-type (WT) control mice. Sestrin2 alleviated increased levels of 24-h urinary protein, blood urea nitrogen, serum creatinine and triglyceride, and urine 8-OHdG in diabetic mice. Podocyte phenotypic alterations, increased expression of apoptosis-associated proteins and podocyte loss were observed in WT but not in diabetic TgN mice, as well as oxidative stress. Additionally, TSP-1/TGF-β1/SMAD3 signaling pathway was also suppressed in glomeruli of diabetic TgN mice. Thus, Sestrin2 mitigates podocyte injury in DKD via orchestrating TSP-1/TGF-β1/SMAD3 pathway, underlining Sestrin2 as a promising therapeutic target for DKD.

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