# Antagonism of Kinin Receptors B1 and B2 Attenuates Folic Acid‐Induced Tubulointerstitial Fibrosis in Mice

## TL;DR

Blocking kinin B1 and B2 receptors in mice shows different effects on kidney injury and scarring over time, suggesting new treatment possibilities for chronic kidney disease.

## Contribution

The study reveals distinct, time-dependent roles of B1R and B2R in modulating inflammation and fibrosis in kidney disease.

## Key findings

- B2R antagonism reduced chronic kidney damage by downregulating proinflammatory mediators.
- B1R blockade worsened acute injury but improved long-term kidney function and reduced fibrosis.
- The findings suggest potential targets for antifibrotic therapies in chronic kidney disease.

## Abstract

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.

Chronic kidney disease affects millions of people and often worsens because of long‐term inflammation and scarring in the kidneys. This study used mice to test how two inflammation‐related proteins, called kinin B1 and B2 receptors, influence kidney damage. Blocking the B2 receptor did not help early kidney injury but reduced long‐term inflammation. Blocking the B1 receptor made early injury worse but later improved kidney function and reduced scarring. These findings show that the two receptors play different roles over time and may help guide future treatments.