Regression of Glomerular Injury by Kallikrein Infusion in Dahl Salt-Sensitive Rats Is a Bradykinin B₂-Receptor-Mediated Event

Abstract

Aims: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B₂) receptor specific antagonist. Methods: Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. Results: Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B₂-receptor antagonist, HOE-140. Conclusion: Long-term infusion of subdepressor dose of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B₂ receptor.

Role of Bradykinin in Renoprotective Effects by Angiotensin II Type 1 Receptor Antagonist in Salt-Sensitive Hypertension.

“…Furthermore, these changes were completely abolished by additional infusion of HOE-140 (33). Taken together with our present findings, these results suggest that activation of bradykinin is critical to prevent and/or buffer glomerular injury caused by salt-sensitive hypertension.…”

Kinin Infusion Prevents Renal Inflammation, Apoptosis, and Fibrosis via Inhibition of Oxidative Stress and Mitogen-Activated Protein Kinase Activity

“…[17][18][19] Similarly, long-term infusion of tissue kallikrein into DSS rats has been shown to attenuate salt-induced renal injury without an apparent effect on blood pressure. 8 These combined data indicate that the tissue kallikrein-kinin system has the ability to exert organ protection independent of its blood pressure-lowering ability. In this study, kinin infusion (500 ng/h) prevented saltinduced renal dysfunction, glomerulosclerosis, tubular damage, and perivascular remodeling in DSS rats.…”

“…7,8 The protective effect of the kinin B2 receptor against kidney injury and fibrosis has also been demonstrated in B2 receptor knockout mice. 9,10 However, the in vivo results conflict with studies of kinins in vitro.…”

Effect of Mycophenolate Mofetil on Kallikrein Expression in the Kidney of 5/6 Nephrectomized Rats

“…Moreover, kallikrein infusion increased the urinary excretion of bradykinin and stimulated the excretion of cyclic GMP, suggesting that the KKS-prostaglandin and KKSnitric oxide axes were enhanced by kallikrein infusion [36]. The renal protection observed after kallikrein infusion was an event mediated by B2 receptors since these beneficial effects were completely abolished by concomitant infusion of the kinin B2 receptor antagonist HOE140 [37]. Recent experiments in which the kallikrein gene was delivered into rats with 5/6 reduction in renal mass showed that this experimental maneuver attenuates hypertension and protects Nx rats against renal injury and cardiac remodelling [38].…”