Glomerular and tubular effects of nitric oxide (NO) are regulated by angiotensin II (Ang II) in an age-dependent manner through activation of both angiotensin receptors (AT1Rs and AT2Rs) in conscious lambs
Renin-angiotensin (RAS) and nitric oxide (NO) systems and the balance and interaction between them are considered of primary importance in maintaining fluid and electrolyte homeostasis. It has been suggested that the effects of NO may be modulated at least in part by the angiotensin (Ang) II, yet the roles of angiotensin receptor type 1 (AT1R) and type 2 (AT2R) are not well understood. Even though both Ang II and NO are elevated at birth and during the newborn period, their contribution to the adaptation of the newborn to life after birth as well as their physiological roles during development are poorly understood. The aim of this study was to determine if NO regulation of renal function during postnatal maturation is modulated by Ang II through activation of AT1R or AT2R or both receptors. Glomerular and tubular effects of either AT1R selective antagonist ZD 7155, AT2R selective antagonist PD 123319, and both antagonists ZD 7155 plus PD 123319, were measured in 1- (N = 9) and 6-week-old (N = 13) conscious, chronically instrumented lambs before and after removal of endogenous NO with l-arginine analogue, l-NAME. Two-way analysis of variance (ANOVA) procedures for repeated measures over time with factors age and treatment were used to compare the effects of the treatments on several glomerular and tubular variables in both groups. This study showed that l-NAME infusion after pre-treatment with ATR antagonists did not alter glomerular function in 1- or 6-week-old lambs. NO effects on electrolytes handling along the nephron during postnatal development were modulated by Ang II through AT1R and AT2R in an age-dependent manner. Selective inhibition of AT1R and AT2R increased excretion of Na+, K+, and Cl− in 6- but not in 1-week-old lambs. In 6-week-old lambs, urinary flow rate increased by 200%, free water clearance increased by 50%, and urine osmolality decreased by 40% after l-NAME was added to the pre-treatment with ZD 7155 plus PD 123319. When l-NAME was added either to ZD 7155 or PD 123319, the same trend in the alterations of these variables was observed, albeit to a lower degree. In conclusion, in conscious animals, during postnatal maturation, Ang II modulates the effects of NO on glomerular function, fluid, and electrolyte homeostasis through AT1Rs and AT2Rs in an age-dependent manner. Under physiological conditions, AT2Rs may potentiate the effects of AT1R, providing evidence of a crosstalk between ATRs in modulating NO effects on fluid and electrolyte homeostasis during postnatal maturation. This study provides new insights on the regulation of renal function during early postnatal development showing that, compared with later in life, newborns have impaired capacity to regulate glomerular function, water, and electrolyte balance.
Newborn Angiotensin receptor Angiotensin II Nitric oxide Electrolytes Renal function Development
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This work was supported by an Operating Grant provided by the Canadian Institutes for Health Research. At the time of these studies, AEV was a doctoral candidate supported by the CIHR Training Program in Genetics, Child Development, and Health, Queen Elizabeth II, and Faculty of Graduate Studies graduate awards. The authors gratefully acknowledge Dr. Wei Qi and Mrs. Lucy Yu for technical assistance with the animals.
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Conflict of interest
The authors declare that they have no conflict of interest.
Supplemental Fig. 1Experimental protocol flowchart. Three experiments were carried out in each animal in random order. Experiments consisted in: (i) Baseline. The baseline period allowed the animal to become accustomed to the experimental environment and stabilization of the hemodynamic variables. Urine was allowed to drain freely during this period; (ii) control period. Fluids were infused to maintain fluid and electrolyte balance and continuous recording and storing of the hemodynamic variables was commenced; (iii) infusion of ATR antagonists, either the AT1R antagonist, ZD 7155, the AT2R antagonist, PD 123319, or both antagonists, ZD 7155 and PD 123319; (iv) infusion of l-arginine analogue, l-NAME. During the experimental periods, in addition to the recording of hemodynamic variables, whole blood and urine were collected at mid-intervals for further analyses. (PDF 19 kb).
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