Single-Agent Treatment with an ALK5 Inhibitor or an SGLT2 Inhibitor (Dapagliflozin) Attenuates Renal Fibrosis in the UUO Mouse Model

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Single-Agent Treatment with an ALK5 Inhibitor or an SGLT2 Inhibitor (Dapagliflozin) Attenuates Renal Fibrosis in the UUO Mouse Model

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Taishi Hashiguchi hashiguchi@smclab.co.jp SMC Labolatories R&D Ota-city Japan *

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Introduction

Tubulointerstitial fibrosis is a major pathological driver of chronic kidney disease (CKD) progression. The TGF-β/ALK5 signaling pathway plays a central role in fibrotic processes, and ALK5 inhibition has been reported to suppress fibrosis in various experimental models. In parallel, SGLT2 inhibitors such as dapagliflozin are increasingly recognized for their renoprotective effects that are independent of glucose lowering. This study aimed to evaluate the antifibrotic efficacy of ALK5 or SGLT2 inhibitor in a unilateral ureteral obstruction (UUO) mouse model.

Methods

Female C57BL/6J mice underwent UUO surgery and were assigned to three groups: vehicle, ALK5 inhibitor, and dapagliflozin. Each compound was administered orally for 14 days from the day of surgery. At Day 14, the left kidney was harvested for evaluation of kidney weight ratio, Sirius Red–positive area, hydroxyproline content, α-SMA–positive cell counts, and fibrosis-related gene expression (TGF-β, Collagen type I, TIMP-1).

Results

Both ALK5 inhibitor and dapagliflozin treatment groups showed reduced fibrosis compared to the vehicle group. Histological analyses demonstrated decreased collagen deposition and Sirius Red–positive area, while gene expression analyses revealed suppressed expression of fibrosis-related genes. These findings indicate clear antifibrotic activity for both single agents in this model.

Conclusion

Single-agent treatment with either an ALK5 inhibitor or dapagliflozin significantly attenuated renal fibrosis in the UUO model. Targeting TGF-β/ALK5 signaling or SGLT2 inhibition represents a promising therapeutic strategy to slow CKD progression, and further studies in chronic kidney injury models are warranted.

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