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

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.

Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy

“…Besides, Sesn2 -/was associated with podocyte loss and decreased expression of synaptopodin, a marker of differentiated podocytes [98]. Similarly, Bian et al and Song et al indicated that Sestrin2 overexpression could ameliorate renal function and decrease creatinine, blood urea nitrogen, and albuminuria in diabetic mice [62,63]. Overexpression of Sestrin2 also attenuated oxidative stress, reduced transforming growth factor beta (TGF-β) expression, and prevented glomerular hypertrophy, mesangial expansion, and extracellular matrix deposition in diabetic mice in these studies (Figure 3) [62,63].…”

“…Similarly, Sestrin2 overexpression attenuated oxidative stress in human mesangial cell exposed to high glucose [62]. Sestrin2 overexpression also attenuated oxidative stress and apoptosis in murine podocyte culture exposed to high glucose [63]. Using a mouse model of diabetic nephropathy, it was shown that attenuation of oxidative stress by Sestrin2 overexpression reversed high glucose-mediated podocyte loss and podocyte malfunctioning [63].…”

“…Using a mouse model of diabetic nephropathy, it was shown that attenuation of oxidative stress by Sestrin2 overexpression reversed high glucose-mediated podocyte loss and podocyte malfunctioning [63]. High glucose exposure downregulated podocyte markers such as synaptopodin and nephrin in the kidney of diabetic mice, while Sestrin2 overexpression maintained their expression [63].…”

“…Previously, it was found that patients with diabetic nephropathy have markedly decreased expression of Ses-trin2 in their kidneys compared with their nondiabetic subjects [9,63]. In particular, patients with diabetic nephropathy have reduced expression of Sestrin2 in their podocytes [9].…”

Breviscapine alleviates podocyte injury by inhibiting NF-κB/NLRP3-mediated pyroptosis in diabetic nephropathy

“…Diabetes was induced by intraperitoneal (i.p.) injections of STZ (Aladdin, Shanghai, China) at a dose of 50 mg/kg for 5 consecutive days, as previously described ( Lee et al, 2022 ; Song et al, 2022 ; Zhong et al, 2019 ). Mice with blood glucose >16.7 mmol/L were considered diabetic 3 days after the injection ( He et al, 2013 ).…”