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

INTRODUCTION: Nitric oxide (NO) vasodilation critically modulates renal hemodynamics in the neonate compared with the adult. Based on the postnatal expression pattern of renal neuronal nitric oxide synthase (nNOS), the hypothesis was that nNOS is the major NOS isoform regulating renal hemodynamics in the immature, but not mature, kidney. RESULTS: NOS inhibitors did not alter mean arterial pressure (MAP) in either group. Intrarenal S-methyl-L-thiocitrulline (L-SMTC) in newborns significantly reduced renal blood flow (RBF) 38 ± 4%, glomerular filtration rate (GFR) 42 ± 6%, and increased renal vascular resistance (RVR) 37 ± 7%, whereas intrarenal L-nitro-arginine methyl ester (L-NAME) affected RBF, GFR, and RVR equivalent to L-SMTC treatment. When L-NAME was administered after L-SMTC treatment, newborn renal hemodynamic changes were not further altered from what was observed when L-SMTC was administered alone. In contrast, in the adult, only intrarenal L-NAME, and not L-SMTC, affected renal hemodynamic responses. DISCUSSION: In conclusion, these studies demonstrate that nNOS is an important regulator of renal hemodynamics in the newborn kidney, but not in the adult. METHODS: Experiments compared renal hemodynamic responses with intrarenal infusion of L-NAME, an inhibitor of all NOS isoforms, with the selective nNOS inhibitor L-SMTC in the newborn piglet and the adult pig.

Angiotensin II regulates NOS expression in afferent arterioles of the developing porcine kidney.

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.

Role of RIHP and renal tubular sodium transporters in volume retention of pregnant rats.

BACKGROUND: Normal pregnancy is characterized by sodium and water conservation and an increase in plasma volume that is required for an uncomplicated pregnancy. Renal interstitial hydrostatic pressure (RIHP) is significantly decreased in pregnant rats. This decrease in RIHP may play an important role in the sodium and water retention that characterizes normal pregnancy. Paradoxically this enhanced renal sodium and water reabsorption appear to conflict with the consistent findings of a general decrease in abundance of renal tubular sodium transporters during normal pregnancy. The objective of this review is to examine the apparent discrepancy between the increases in renal tubular sodium and water reabsorption, facilitated by decreases in RIHP, and the seemingly discordant decreases in abundance of renal tubular transporters during normal pregnancy in rats. METHODS: Western blots and immunohistochemistry were used to evaluate abundance and localization of renal tubular transporters. RIHP was measured directly and continuously via a polyethylene (PE) matrix that was implanted in the left kidney of rats at the age of 11 to 16 weeks. RESULTS: Average basal RIHP and fractional excretion of sodium (FENa) were found to be significantly lower (P < .05) in midterm pregnant (MP; n = 18) and late-term pregnant (LP; n = 20) rats compared with nonpregnant (NP; n = 16) rats (3.5 +/- 0.3 mm Hg and 1.46 +/- 0.24% for MP; 3.3 +/- 0.1 mm Hg and 1.41 +/- 0.21% for LP; and 7.6 +/- 0.6 mm Hg and 3.67 +/- 0.24% for NP). Cortical Na+-K+-ATPase and Na-Pi2a cotransporter (Na-Pi) protein expression tend to decline with pregnancy. Also cortical Na+-H+ exchanger-1 (NHE-1) protein expression declines steadily during the course of pregnancy from MP to LP compared with that in NP rats, and cortical Na+-H+ exchanger-3 (NHE-3) protein expression is significantly lower in MP and LP compared with NP rats. CONCLUSIONS: We propose that during normal uncomplicated pregnancy, simultaneous decreases in RIHP and in net abundance of renal tubular sodium transporters occur. The effects of decreased RIHP exceed those of the reduction in net abundance, and presumably activity, of renal tubular transporters resulting in an enhanced net sodium and water retention during pregnancy.

The developing kidney and environmental toxins.

The effects of environmental chemicals, drugs, and physical agents on the developing kidney are influenced by the state of renal development and maturation. The development of the kidney, the major excretory organ after birth, consists of 3 stages: the pronephros, or cervical kidney; mesonephros, or thoracic kidney; and metanephros, or abdominal kidney, the definitive kidney. In humans, nephrogenesis and organogenesis occur from the 6th to the 36th weeks of gestational age. After 36 weeks, nephrogenesis is complete and each kidney has a full complement of nephrons. The extent of chemical-induced renal toxicity is related, in part, to the efficiency in which the particular compound is transported by renal tubules. Because renal tubular transport capacities vary with maturation, the degree of nephrotoxicity may also vary with maturation. The signs and symptoms of nephrotoxicity can appear acutely or insidiously. Unexplained acute renal failure, chronic mild proteinuria, or even hypertension can be a manifestation of nephrotoxic agents. Species differences occur, thus the need for studies in humans.

Renal interstitial hydrostatic pressure and natriuretic responses to volume expansion in pregnant rats.

During normal pregnancy, a gradual plasma volume expansion (VE) occurs and reaches a maximum level at late term. Pressure natriuresis and renal interstitial hydrostatic pressure (RIHP) responses are attenuated in pregnant rats. Also, basal RIHP is lower in pregnant rats, suggesting an increase in renal interstitial compliance during pregnancy. This adaptation may contribute to the increase in plasma volume that is required for a normal pregnancy, because increases in RIHP have been consistently shown to produce natriuresis and diuresis. Acute saline VE (5% body wt/30 min) has been shown to increase RIHP in normal nonpregnant rats. Therefore, the objective of this study was to determine RIHP, natriuretic, and diuretic responses to VE in nonpregnant (n = 7), midterm pregnant (n = 8), and late-term pregnant (n = 8) Sprague-Dawley rats. Although VE significantly increased RIHP, fractional excretion of sodium (FE(Na)), and urine flow rate (V) in all groups, DeltaRIHP was highest for nonpregnant (3.0 +/- 0.3 mmHg) compared with midterm pregnant (1.6 +/- 0.1 mmHg; P < 0.05 vs. nonpregnant) and late-term pregnant rats (1.2 +/- 0.1 mmHg; P < 0.05 vs. both midterm pregnant and nonpregnant rats). DeltaFE(Na) and DeltaV were similar in all groups: 5.8 +/- 1.0% and 231 +/- 27 microl/min for nonpregnant, 6.8 +/- 1.3% and 173 +/- 16 microl/min for midterm pregnant, and 7.6 +/- 1.2% and 203 +/- 10 microl/min for late-term pregnant rats, respectively. In conclusion, basal RIHP and the increase in RIHP during VE were attenuated during pregnancy; however, the natriuretic and diuretic responses to VE remain intact during the course of pregnancy.