Kinin B1 Receptor as a Central Mediator of Kidney Injury in Hypertension

Background: Chronic hypertension is a major driver of progressive renal damage and is the leading cause of chronic kidney disease (CKD). However, the molecular mechanisms linking hypertensive signaling to fibrotic remodeling and kidney dysfunction are poorly understood. We previously showed that the kinin B1 receptor (B1R) is implicated in salt-sensitive hypertension-induced renal inflammation and oxidative damage. However, the relevance of B1R signaling in renin angiotensin system (RAS) driven hypertensive nephropathy remains unknown. Methods: De-identified, formalin fixed paraffin embedded kidney biopsies from normotensive (NTN) and hypertensive CKD patients (HTN, stage 3-4) were obtained from the biorepository of the Department of Pathology, East Carolina University. To study RAS driven hypertensive nephropathy, C57Bl/6NJ (WT) and B1R knockout (B1RKO) mice received saline or angiotensin II (Ang II, 600ng/kg/min, SC) for 28 days. Results: B1R expression was increased in HTN kidneys compared to NTN and was positively correlated with collagen deposition, interstitial fibrosis and tubular atrophy, and glomerulosclerosis. Kidney to body weight ratios were elevated in HTN patients, suggesting hypertrophy. Additionally, proximity ligation assay revealed spatial B1R-AT1R interactions within fibrotic regions, suggesting a possible mechanism for amplified profibrotic and inflammatory signaling in hypertensive CKD. To further study this, WT and B1RKO mice underwent Ang II infusion for 28 days. WT mice given Ang II developed renal hypertrophy, oxidative stress, collagen deposition, and increased B1R and AT1R expression. Furthermore, B1R co-localized with nephrin (podocytes), SGLT2 (proximal tubule), AQP2 (collecting duct), and ECaC (distal tubule), indicating its widespread involvement in both glomerular and tubular components. Notably, B1RKO mice were protected from Ang II-induced renal hypertrophy, fibrosis, and oxidative stress. Conclusion: B1R serves as a central mediator of hypertensive kidney injury, possibly through its interactions with AT1R to promote fibrosis, oxidative stress, and nephron dysfunction. These findings suggest that B1R may be a novel therapeutic target to mitigate renal damage and slow CKD progression in hypertensive patients. Funding: Other NIH Support - Research Project Grant (R01) funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health (NIH).