Antagonism of Kinin Receptors B1 and B2 Attenuates Folic Acid-Induced Tubulointerstitial Fibrosis in Mice.

Chronic kidney disease (CKD) remains a significant global health burden despite recent advances in pharmacotherapy, including sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists. Renal fibrosis, a central pathological hallmark of CKD progression, is mediated by persistent inflammation and macrophage activation, wherein the kallikrein-kinin system-particularly kinin receptors-plays a critical role. Emerging evidence supports the therapeutic potential of dual kinin receptor antagonism, especially targeting B1R, though the precise molecular mechanisms remain incompletely understood, necessitating further investigation. To elucidate the role of kinin receptors in renal injury, male C57BL/6 mice were subjected to folic acid-induced nephropathy and treated with either the B1R antagonist R715 or the B2R antagonist HOE140. Treatments were administered pre- and postfolic acid injection. Renal function was evaluated via serum creatinine, blood urea nitrogen and urine analyses. Renal tissues underwent histopathological assessment and gene expression profiling to assess injury and fibrotic responses. B2R antagonism (HOE140) failed to attenuate acute tubular injury but ameliorated chronic damage by downregulating proinflammatory mediators and upregulating anti-inflammatory markers. In contrast, B1R blockade (R715) exacerbated acute kidney injury yet mitigated chronic fibrosis, improving renal function and reducing profibrotic gene expression. These findings delineate distinct, time-dependent roles of B1R and B2R in modulating macrophage polarization (M1/M2) and fibrogenesis, identifying potential targets for antifibrotic therapies.