Long-term infusion of kallikrein attenuates renal injury in Dahl salt-sensitive rats.

Abstract

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive rats. A subdepressor dose of purified rat urinary kallikrein (700 ng/d IV) was infused by osmotic minipump for 4 weeks in male Dahl salt-sensitive rats fed a high salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure; however, urinary protein excretion was significantly decreased, and glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl salt-sensitive rats. Kallikrein infusion increased urinary A ngiotensin-converting enzyme (ACE) inhibitors affect both the renin-angiotensin and kallikrein-kinin-prostaglandin systems, inhibiting different catalytic sites on the same ACE. The cardiovascular protection induced by ACE inhibitors is primarily due to inhibition of the renin-angiotensin system. Recent advances in vascular biology suggest that the vasodepressor system participates in the progression or regression of cardiovascular injury.12 Vasodepressor eicosanoid directly delays the transition from the resting G0/G1 to DNA-synthetic (S) period progression in the proliferative cycle of vascular smooth muscle cells. 3 Moreover, enhancement of the endogenous production of prostacyclin attenuates vascular and renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats, a genetic model for salt-induced hypertension in humans. 4 Kinins stimulate the formation of nitric oxide, which also retards vascular smooth muscle cell proliferation. 56 The activity of the kallikrein-kinin-prostaglandin system is reduced in the kidneys of Dahl S rats. "9 Recently, kallikrein-like activity and its corresponding mRNAs have been found in the vascular wall.1012 More intriguingly, it has been reported that blood pressure cosegregates with a kallikrein gene restrictive fragment length polymorphism.13 These data Correspondence to Yoshio Uehara, MD, The Second Department of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.© 1994 American Heart Association, Inc.excretion of bradykinin and stimulated excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by rat urinary kallikrein infusion. The alterations induced by kallikrein infusion were potentiated by the concomitant administration of the angiotensin-converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl salt-sensitive rats. (Hypertension. 1994;24:770-778.) Key Words • kallikrein • renin-angiotensin system • rats, inbred Dahl • angiotensin-converting enzyme inhibitor • prostaglandins • kallikrein-kinin system clearly suggest that dysfunction of the kallikrein-kininprostaglandin system is involved in the genesis of saltinduced hypertension of Dahl S rats.We have ...

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