Abstract: Objective To investigate the potential mechanism of canagliflozin alleviating renal fibrosis in diabetic nephropathy mice through PDGF / SIRT1. Methods The diabetic nephropathymouse model was established using streptozotocin ( STZ), and the following groups were set up:① control mice, ② STZ mice, ③ STZ mice treated with canagliflozin, ④ BSA treated STZ mice,⑤ STZ treated with PDGF antibody, ⑥ STZ mice co-treated with canagliflozin and BSA, ⑦ STZmice co-treated with canagliflozin and PDGF antibody. The kidney tissues and serum of mice in eachgroup were collected. The mRNA and protein expression levels of myofibroblast markers (type I collagen, fibronectin, α-SMA ) were detected. The mitochondrial biogenesis indicators ( the mitochondrial DNA copy number and the expression levels of key regulatory factors SIRT1 and differentsubunits of electron transport chain proteins) were analyzed. And the levels of serum PDGF weremeasured. Results STZ significantly enhanced the mRNA and protein expression levels of type Icollagen, fibronectin and α-SMA. However, the expression levels of these myofibroblast markerswere returned to normal levels after canagliflozin treatment. STZ reduced mitochondrial DNA copynumber, and canagliflozin prevented this decline. At the same time, STZ-induced reductions in SIRT1, PHB1, HSP60, VDHC, SDHA, and Cox IV were blocked by canagliflozin. Furthermore, the STZ-induced rise in PDGF level was restored by the presence of canagliflozin. The expression level of SIRT1 in the kidneys of STZ and PDGF co-treated mice was lower and the mRNA expression levels of myofibroblast markers were higher, when compared with those in the kidneys of of STZtreated mice. And there were no significant differences in the expression levels of SIRT1 and mRNA expression levels of myofibroblast markers in the kidneys of mice co-treated with STZ, PDGF and canagliflozin, when compared with those of the STZ mice co-treated with canagliflozin andBSA. Conclusion Canagliflozin therapy can reduce renal fibrosis in diabetic nephropathy mice andthe mechanism is dependent on the PDGF / SIRT1-mediated mitochondrial biogenesis axis.

Key words: canagliflozin, PDGF, SIRT1, diabetic nephropathy, renal fibrosis