RENIN, ANGIOTENSINOGEN, AND KALLIKREIN GENE-EXPRESSION IN 2-KIDNEY GOLDBLATT HYPERTENSIVE RATS

An imbalance in the activity of the vasopressor renin-angiotensin and vasodepressor kallikrein-kinin systems may play an important role in t he pathogenesis of hypertension after unilateral renal artery constric tion. To test this hypothesis, we examined the expression of the renin , angiotensinogen (Ao), and tissue kallikrein genes 7 and 25 days afte r placement of a 0.25-mm clip on the left renal artery of rats. One we ek after clipping, renin mRNA levels were 4.6-fold higher in the clipp ed and 50% lower in the nonclipped kidneys compared with kidneys from sham-operated rats. At 25 days, renin mRNA levels in the clipped kidne ys were not different from sham kidneys, but were suppressed to almost undetectable levels in the nonclipped kidneys. Steady-state Ao mRNA l evels in the clipped kidneys were not different from those of nonclipp ed or sham kidneys at either 7 or 25 days. However, at 25 days, Ao mRN A levels were lower in the liver (70%), left ventricle (55%), and aort a (45%) of clipped than sham-operated rats. The expression of the rena l kallikrein gene was unchanged at 7 days and was suppressed by 50% at 25 days. These results are consistent with the notion that activation of the intrarenal renin-angiotensin system occurs during the initial phase of the two-kidney, one-clip hypertension model. The renal kallik rein gene, in marked contrast to renin, becomes downregulated in the c hronic phase. The differential regulation of renin-angiotensin and kal likrein genes may be an important pathogenetic factor in renovascular hypertension. Importantly, the sustained Ao mRNA in the kidneys contra sts with the downregulation of extrarenal Ao gene expression and may c ontribute to the sustained tissue angiotensin II production even in th e presence of marked suppression of renin synthesis.