Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: potential role of klotho expression

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Abstract
Chronic kidney disease (CKD) is a global healthcare problem; however until now, there is no effective treatment that can stop its progression. In this study, we aimed to investigate the effect of empagliflozin, a sodium-glucose linked transporter-2 inhibitor (SGLT2I) in a model of unilateral ureteric obstruction (UUO) in rats, as a model of progressive renal interstitial fibrosis in vivo and the possibility of inclusion of klotho protein. Rats were randomly divided into five groups: group 1: control group, group 2: UUO untreated group, group 3: prophylactic SGLT2I treatment before UUO, group 4: immediate SGLT2I treatment after UUO, and group 5: delayed SGLT2I treatment (this group received distilled water 1 week after UUO then empagliflozin for 2 weeks). At the end of the experiment period, animals were sacrificed, and kidney fibrotic and inflammatory parameters were measured. Also kidney sections were examined histopathologically for CTGF expression. UUO resulted in renal dysfunction and fibrosis through upregulating inflammatory cascade (NF-κB-TLR4) as well as many fibrotic pathways (as TGF-β1, αSMA, Wnt, CTGF, and fibronectin) with significant reduction in the klotho protein expression. We hypothesized that both prophylactic and immediate treatment with empagliflozin after UUO in rats exert more renoprotective effect in comparison with delayed treatment via enhancement of renal klotho expression and activity, for further investigations.

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