Angiotensin II (Ang II) has growth promoting effects in a number of cells and tissues in vitro. The purpose of this study was to examine the in vivo effect of Ang II on the renal expression of the early growth response genes c-fos, Egr-1 and C-JMK. Adult male rats underwent two basal 30 minute clearance periods during which the normal saline vehicle was infused into the left renal artery. Normal saline, Ang II (50 ng/kg/min), or Ang II plus the Ang II antagonist Sar1 Gly8-angiotensin II (10 μg/kg/min) were then selectively infused into the left renal artery for two additional 30 minute periods. MAP was similar during basal and Ang II infusion. Hemodynamic effects (decrease in GFR and RPF and increase in renal vascular resistance) were observed only in the Ang II-infused left kidney allowing the right kidney to serve as a paired control for the effects of anesthesia and surgery. Significant increases in the expression of the early growth response genes Egr-1 and c-fos, but not c-jun, were found in the Ang II-infused left kidney compared to the control right kidney. The simultaneous infusion of Ang II (50 ng/kg/min) and the Ang II antagonist Sar1 Gly8-angiotensin II (10 μg/kg/min) blocked the increase in Egr-1 and c-fos expression, demonstrating the specificity of the response to Ang II. To compare the effect of another renal vasoconstrictor on the expression of early growth response genes, norepinephrine (40 ng/kg/min) was infused into the left renal artery. This dose lacked a systemic pressor effect, produced vasoconstriction in the infused left kidney, but did not alter hemodynamics of the right kidney. Norepinephrine significantly increased Egr-1 and c-fos and c-jun mRNA. In conclusion, intrarenal infusion of Ang II and norepinephrine induced early growth response genes in the kidney, an effect associated with cellular growth in other tissues. The similarity of the response to two different vasoconstrictors raises the possibility that early growth responses may be transduced, in part, from renal hemodynamic effects.
Bibliographical noteFunding Information:
This work was supported by US Public Health Service Grants AM-3l437 (T.H.H.) and R29DK43075 (M.E.R.), and by a Young Investigator Grant from the National Kidney Foundation (M.E.R.). We thank Vikas Sukhatme and Daniel Nathans for the Egr-1 and c-jun probes.