Tadalafil protects against renal fibrosis after ischemia-reperfusion injury by inhibiting Akt/NF-κB signaling pathway.

Renal fibrosis is a common feature of chronic kidney diseases, characterized by a complex and dynamic process involving the infiltration of inflammatory cells, abnormal formation and deposition of the extracellular matrix, and damage to the kidney's intrinsic cells. Renal fibrosis can lead to end-stage renal disease, but developing antifibrotic drugs remains a significant challenge. Phosphodiesterase 5 inhibitors have anti-apoptotic and antioxidant properties, making them promising candidates for treating ischemia-reperfusion injuries. However, no phosphodiesterase 5 inhibitors are currently approved for kidney disease treatment. This study evaluated the therapeutic effects of Tadalafil, a long-acting phosphodiesterase 5 inhibitor, in a murine model of unilateral renal ischemia-reperfusion injury. Mice underwent 45 min of renal ischemia followed by reperfusion and were then randomized to receive Tadalafil (1 mg/kg/day or 3 mg/kg/day) via oral gavage or vehicle control. Treatment began 2 h post-injury and continued for 11 consecutive days. The results showed that Tadalafil could reduce excessive extracellular matrix deposition and inflammatory cell infiltration, as well as improve renal tissue structural damage and glomerular filtration function. Furthermore, Tadalafil significantly inhibited mesangial cell proliferation and activation induced by Angiotensin II. Mechanistically, Tadalafil was found to inhibit the activation of the Protein Kinase B (Akt)/Nuclear Factor kappa-B (NF-κB) signaling pathway, thereby exerting its therapeutic effects on renal fibrosis. These findings confirm that Tadalafil protects against ischemia-reperfusion-induced renal injury by inhibiting mesangial cell activation and modulating the Akt/NF-κB pathway, supporting the potential of phosphodiesterase 5 inhibitors as a novel therapeutic option for renal fibrosis.