Metformin attenuates renal interstitial fibrosis through upregulation of Deptor in unilateral ureteral obstruction in rats

Abstract

Renal interstitial fibrosis (RIF) is a common pathological process that accompanies chronic kidney disease (CKD) and that progresses to end-stage renal failure (ESRD). Accumulating evidence has revealed that persistent mammalian target of rapamycin (mTOR) activation in kidneys is closely associated with the occurrence and progression of CKD. The DEP domain-containing mTOR interacting protein (Deptor) is an endogenous negative regulator of mTOR. Metformin can attenuate renal fibrosis in an animal model of diabetic nephropathy. Previous studies demonstrated that metformin can attenuate renal fibrosis in several models of CKD. However, the precise mechanisms of this effect are not well understood. The present study aimed to examine the mechanism of action of metformin on unilateral ureteral obstruction (UUO)-induced RIF in rats in vivo. Sprague-Dawley rats were randomly divided into a sham-operated group, three UUO groups examined at different time points (3, 7 and 14 days after UUO surgery), and three metformin-treated groups, treated with three different concentrations of metformin. The metformin-treated groups were administered metformin orally every day for 14 consecutive days following surgery. The protein expression levels of Deptor, α-smooth muscle actin (α-SMA), phosphorylated (p-)mTOR, p-ribosomal protein S6 kinase (p-p70S6K) and CD68 were assessed. The present results suggested that, following UUO, there was a significant reduction of Deptor expression, and an increase in collagen deposition in the extracellular matrix over time, accompanied by an increased expression of several proteins including CD68, α-SMA, p-mTOR and p-p70S6K. Notably, metformin treatment reversed these effects. In conclusion, the present results suggested that metformin attenuated RIF of UUO rats, and the mechanism of action was found to be associated with the increase in Deptor expression and inhibition of the mTOR/p70S6K pathway in the kidneys of UUO rats.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

“… 7 , 8 , 12 Renal protection with MF has also been observed in numerous experimental models ranging from diabetic-associated or obesity-associated kidney disease (∼300 indexed citations), other proteinuric kidney diseases (lupus nephritis, 13 , 14 Alport’s syndrome, 15 and subtotal nephrectomy 16 , 17 ), as well as nonproteinuric kidney diseases. 18 , 19 , 20 , 21 , 22 , 23 Therefore, extensive preclinical data demonstrate the benefit of MF in renal disease, and our work supports a specific role for AMPK in podocyte survival after injury.…”

Use of Anti-Diabetic Agents in Non-Diabetic Kidney Disease: From Bench to Bedside

“…The DEP domain-containing mTOR interacting protein (DEPTOR) is an endogenous negative regulator of mTOR that inhibits the kinase activity of both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. According to Wang et al, metformin attenuated renal interstitial fibrosis by increasing DEPTOR expression and inhibiting the mTOR/p70S6K pathway in the kidneys of UUO rats [38]. Because metformin limited the infiltration of immune cells into the UUO kidney, systemic immunomodulatory action was suggested, probably via inhibition of signal transducer and activator of transcription 3 (STAT3) activity [39].…”

Metformin inhibits EV71‑induced pyroptosis by upregulating DEP domain‑containing mTOR‑interacting protein

“…Previous studies suggest that metformin can increase DEP domain-containing mTOR-interacting protein (DEPTOR) levels in hepatoma cells, ureteral epithelial cells and rats with unilateral ureteral obstruction (25,26). DEPTOR is a component of the mTOR complex (mTORC)1 and mTORC2 and binds to mTOR to suppress its kinase activity (27).…”