Abstract
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 Na+ retention contributes to the development of hypertension in the LP rat (offspring exposed to a maternal low-protein diet in utero). However, this hypothesis has not been tested in vivo. Renal clearance measurements in hypertensive 4-week-old male and female LP rats showed that, although the glomerular filtration rate remained unaltered, urine flow (P < 0.01) and urinary Na+ excretion rates (1.6 +/- 0.3 and 3.0 +/- 0.4 mu mol . min(-1) . 100 g(-1) of body weight in control male and LP male respectively; P < 0.001) were increased. Na+ excretion was positively correlated with mean arterial pressure in both males (P < 0.01) and females (P < 0.05), but neither the slope nor the intercept differed between control and LP rats. Fractional excretion of Na+ was increased in male (1.5 +/- 0.2 and 3.0 +/- 0.5% in control and LP rats respectively; P < 0.001) and female LP rats, implying reduced tubular reabsorption of Na+. Western blotting and quantitative PCR showed that NKCC2 expression was increased, whereas NCC mRNA was not up-regulated. Na+/K+ ATPase alpha(1) subunit expression did not differ from controls; however, there was a significant reduction in whole kidney pump activity (23.4 +/- 1.8 and 17.7 +/- 1.2 nmol of phosphate . mu g(-1) of protein . h(-1) in control male and male LP rats respectively; P < 0.001); immunohistochemistry showed that the alpha(1) subunit was virtually absent from the inner medulla. The greater Na+ excretion of LP rats can be explained, in part, by a pressure-natriuresis mechanism; however, the loss of the Na+/K+ ATPase alpha(1) subunit from the inner medulla and up-regulation of NKCC2 suggests that altered renal Na+ handling is also programmed prenatally.