Angiotensin II Regulates NOS Expression in Afferent Arterioles of the Developing Porcine Kidney

Abstract

NO protection is crucial against angiotensin II (ANG II) mediated vasoconstriction in postnatal preglomerular resistance vessels. Although whole kidney NOS is developmentally regulated, NOS regulation in developing renal resistance vessels is unknown. The hypothesis was NOS expression and function in developing afferent arterioles are regulated by ANG II through AT1 and AT2 receptors. Afferent arterioles from porcine kidneys, ages newborn, 7, 21 d, and adult, were dissected using a polybead perfusion technique. Dissected afferent arterioles were treated with ANG II and with either the AT1 receptor inhibitor candesartan or the AT2 receptor inhibitor PD 123319 and evaluated for NOS isoform expression and NOS enzymatic activity. Although NOS activity and neuronal NOS (nNOS) expression were greater in the newborn than in the adult, endothelial NOS (eNOS) expression was greater in the adult. ANG II increased NOS activity and eNOS expression at all ages, but nNOS expression only in developing afferents. AT1 and AT2 receptor blockade significantly attenuated NOS activity and eNOS expression at all ages, but nNOS expression only in developing afferents. ANG II regulates nNOS and eNOS expression and NOS activity in afferent arterioles of the developing kidney via AT1 and AT2 receptors.

Identification and characterization of a functional mitochondrial angiotensin system

“…The RAS influences cardiovascular function via nitric oxide (NO) regulation (6)(7)(8). AT 1 R blockade increases NO, and this increase is abolished by concomitant AT 2 R blockade, suggesting that AT 2 Rs are important in NO production (9).…”

“…AT 1 R blockade increases NO, and this increase is abolished by concomitant AT 2 R blockade, suggesting that AT 2 Rs are important in NO production (9). AT 2 Rs likely increase NO production via direct stimulation of NO synthase (NOS) (10) or indirectly through bradykinin-dependent mechanisms (7). Recently, the intracrine activation of AT 2 Rs has been reported to increase NO production in isolated cortical kidney nuclei (11).…”

Neuronal nitric oxide synthase, nNOS, regulates renal hemodynamics in the postnatal developing piglet

“…However, several characteristics of nNOS in postnatal renal maturation suggest that this isoform may participate significantly in renal hemodynamics in the neonate after birth. In previous studies by our laboratory, we observed both developmentally upregulated NOS enzymatic activity and nNOS mRNA and protein expression in the kidney during the postnatal period (19,20). In fact, NOS enzymatic activity in the preglomerular-resistance vasculature of the newborn is fourfold greater than that of the adult (19).…”

“…NO is known to inhibit cyclic adenosine monophosphate degradation through cyclic GMP-mediated mechanisms, thereby stimulating renin secretion, whereas cellular calcium influx and protein kinase K activation inhibit renin release (36 (3,11,19). In studies by Ratliff et al, it was demonstrated that NO production in the preglomerular resistance vasculature is threefold higher in the newborn than in the adult (19,20). During the newborn's period of increased NO production, eNOS expression is minimally detectable, with protein levels sevenfold less than what is observed in the adult (20).…”

“…During the newborn period of enhanced NO production, basal eNOS expression in renal resistance vessels and throughout the immature kidney is significantly downregulated. However, unlike in the adult, nNOS expression and protein are upregulated within the newborn's renal vasculature, including a sevenfold increase in the afferent arteriole where NO production is significantly enhanced (20). nNOS also exhibits a distinct postnatal maturational expression pattern in the macula densa of the maturing rat, a site that further influences renal hemodynamics (14,21,22).…”