Angiotensin II inhibits growth of cultured embryonic renomedullary interstitial cells through the AT2 receptor

Abstract

The high abundance of angiotensin II (Ang II) AT2, relative to the AT1 receptor subtype in developing kidneys may be related to their potential as mediators of cell growth, although little evidence exists to support this concept. Renomedullary interstitial cells (RMICs) differentiate early in embryonic kidneys and are important in subsequent nephron development. These cells have been shown in vivo to possess AT2 binding sites, although the functional significance of these sites remains unknown. The aim of the current investigation was to examine the actions of Ang II on cultured embryonic renomedullary interstitial cells (ERMICs). 125I-[Sar1, Ile8]Ang II specifically bound to AT1 and AT2 receptors on ERMICs, and their mRNAs were detected by reverse transcription-polymerase chain reaction (RT PCR). Angiotensin II (10-6 M) increased intracellular IP3 concentrations at 20 seconds, and decreased intracellular cAMP concentrations after 10 minutes. Angiotensin II (10-6 M) induced an increase in [3H]thymidine incorporation, mediated through the AT1 receptor subtype. Basic fibroblast growth factor (bFGF; 20 ng/ml) also increased 3[H]thymidine incorporation after 24 hours of treatment, an effect that was attenuated by subsequent addition of Ang II (10-6 M). This antiproliferative action of Ang II was blocked by PD 123319 (10-6 M), an AT2 receptor antagonist, and was not affected by losartan (10-6 M), an AT1 receptor antagonist. These results indicate a dual role for Ang II in regulating ERMIC mitogenesis: a growth stimulating effect mediated by the AT1 receptor subtype, and an antiproliferative effect mediated by the AT2 receptor subtype.