WCN26-6275 Single-Agent Treatment with an ALK5 Inhibitor or an SGLT2 Inhibitor (Dapagliflozin) Attenuates Renal Fibrosis in the UUO Mouse Model

Introduction: Renal interstitial fibrosis represents a final common pathway driving the progression of chronic kidney disease (CKD) to end-stage kidney disease.Following renal injury, infiltration of inflammatory cells and activation of tubular epithelial cells induce the transformation of fibroblasts and pericytes into myofibroblasts, leading to excessive extracellular matrix deposition.To better understand and prevent renal fibrosis, it is essential to identify key factors within interstitial cells that regulate this process.We therefore focused on transcription factor Tcf21 as a potential regulator of renal fibrosis.Tcf21 is essential for organ development, including the heart, kidney and lung, and Tcf21 is expressed in podocytes and interstitial cells in adult kidneys.Although Tcf21 has been reported to exert anti-fibrotic effects in the heart and liver, its functional role in renal fibrosis remains unclear.This study aimed to clarify the role of Tcf21 in regulating renal interstitial fibrosis.Methods: To evaluate Tcf21 expression in interstitial cells, renal fibrosis was induced in mouse kidneys using two established models: unilateral ureteral obstruction (UUO; assessed at 10 days post-surgery) and unilateral ischemia reperfusion injury (uIRI; assessed at 21 days post-surgery).Tcf21 expression was assessed by quantitative real-time PCR (qPCR) and in situ hybridization.To examine the functional role of Tcf21 in interstitial cells, we generated tamoxifen-inducible renal interstitial cell-specific Tcf21 knockout mice (PdgfrCreER; Tcf21flox/ flox, hereafter referred to as istrTcf21 mouse).Kidneys from Control and istrTcf21 mice were evaluated one month after Tcf21 deletion under baseline condition.In a separate injury-model cohort, control and istrTcf21 mice were subsequently subjected to either UUO or uIRI.Renal fibrosis was quantified by the expression of Col1a1 and Acta2 (aSMA) using qPCR analysis and immunostaining.Results: Whole-kidney qPCR analysis showed that Tcf21 mRNA was significantly increased in both UUO and uIRI models compared with their contralateral kidneys.In situ hybridization confirmed that Tcf21 expression was notably increased in interstitial cells.Importantly, Tcf21 expression level was positively correlated with kidney fibrosis.Next, we examined baseline phenotypes in istrTcf21 mice.A successful deletion of Tcf21 in interstitial cells was confirmed, yet no difference in kidney fibrosis was detected between control and istrTcf21 mice by qPCR and immunostaining.In the UUO model, istrTcf21 mice exhibited a mild reduction in interstitial fibrosis with Col1a1 expression decreased by approximately 30% compared with controls.In the uIRI model, loss of Tcf21 significantly attenuated fibrosis.These findings suggest that Tcf21 expression in interstitial cells is induced by kidney injury and promotes fibrotic remodeling.Conclusion: Our data demonstrate that Tcf21 in interstitial cells is induced by kidney fibrosis and that its pre-injury deletion attenuates kidney fibrosis.These results indicate that Tcf21 acts as a pro-fibrotic rather than an anti-fibrotic factor, in contrast to previous findings in heart and liver fibrosis models.Elucidating the mechanism by which Tcf21 regulates renal fibrosis would provide new insights into the potential therapeutic strategies for CKD patients.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.