Prenatal programming of renal sodium handling in the rat
Résumé
Prenatally programmed hypertension induced by maternal protein restriction is associated with increased expression of the renal tubular Na+:K+:2Cl- co-transporter (NKCC2) and the Na+:Cl- co-transporter (NCC). This has led to the suggestion that renal sodium retention contributes to the development of hypertension in the low protein (LP) rat. However, this hypothesis has not been tested in vivo. Renal clearance measurements in hypertensive 4 week old male and female LP rats showed that while glomerular filtration rate remained unaltered, urine flow (P<0.01) and urinary sodium excretion (control male 1.6±0.3 vs LP male 3.0±0.4 µmol.min-1.100g bwt-1, P<0.001) rates were increased. Sodium excretion was positively correlated with mean arterial pressure in both males (P<0.01) and females (P<0.05) but neither the slope nor intercept differed between control and LP rats. Fractional excretion of sodium was increased in male (control 1.5±0.2 vs LP 3.0±0.5%, P<0.001) and female LP rats, implying reduced tubular reabsorption of sodium. Western blot and quantitative PCR showed that NKCC2 expression was increased; NCC mRNA was not upregulated. Na+:K+ATPase α1 subunit expression did not differ from controls, however, there was a significant reduction in whole kidney pump activity (control male 23.4±1.8 vs LP male 17.7±1.2 nM PO4.μg protein-1.h-1, P<0.001); immunohistochemistry showed that the α1 subunit was virtually absent from the inner medulla. The greater sodium excretion of LP rats can be explained, in part, by a pressure natriuresis mechanism. However, loss of the Na+:K+ATPase α1 subunit from the inner medulla and upregulation of NKCC2 suggests that altered renal sodium handling is also programmed prenatally.
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