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Kidney Week

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Abstract: TH-PO489

Kinin in Hypertensive Kidney Disease: A Novel Therapeutic Target

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Basuli, Debargha, East Carolina University, Greenville, North Carolina, United States
  • Parekh, Rohan Umesh, East Carolina University, Greenville, North Carolina, United States
  • Sriramula, Srinivas, East Carolina University, Greenville, North Carolina, United States
Background

Hypertensive kidney disease is the second leading cause of end-stage renal disease (ESRD) following diabetes. While inhibition of the renin-angiotensin system remains the current management of hypertensive kidney disease, we are still spending billions of dollars for hemodialysis and the incidence of ESRD is projected to increase in upcoming years. Thus, elucidating the pathogenesis of hypertensive kidney disease, particularly if there is any non-angiotensin pathway involved is important to formulate newer treatment strategies. Recently, a growing body of evidence suggests a role for kallikrein-kinin system in hypertension and kidney diseases. The effects of kinins are exerted through two G-protein coupled receptors- B1R and B2R. It has been recently shown that B1R regulates neurogenic hypertension in mice. However, the role of B1R in hypertension induced end-organ damage, particularly in the kidney has not been studied. This study examines the significance of B1R induced inflammation and fibrosis in the kidney.

Methods

Human kidney sections were used to study the expression pattern of B1R in kidneys by immunohistochemistry. Deoxycorticosterone acetate (DOCA)-salt hypertension model coupled with a whole body B1R knockout (B1RKO) mice were used to study the effect of kinin B1R blockade on hypertensive kidney disease. Hypertension induced renal damage was assessed by measuring the mRNA and protein expression of fibrosis markers (collagen I/III, fibronectin, TGF-β). Renal inflammation was studied by assaying inflammation markers (TNFa, IL6, IL1b) and inflammatory cell infiltration.

Results

B1R is expressed in human kidneys predominantly in proximal tubular cells. Treatment with DOCA-salt significantly increased blood pressure (p<0.001) in wild-type mice, which was attenuated in B1RKO mice. B1R blockade decreased DOCA-salt-induced renal fibrosis. Moreover, DOCA-salt-induced increase in renal inflammation was significantly blunted in B1RKO mice.

Conclusion

Our data provide evidence that kinin B1R is expressed in human kidney and may have an important role in the pathogenesis of hypertensive kidney disease. In an animal model, B1R knockdown reduces hypertensive renal damage by decreasing inflammation and fibrosis. Kinin B1R offers a potential therapeutic target for the treatment of hypertension and hypertensive kidney disease.