Prenatal programming of renal sodium handling in the rat

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 μmol·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 α₁ 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·μg⁻¹ of protein·h⁻¹ in control male and male LP rats respectively; P<0.001); immunohistochemistry showed that the α₁ 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 α₁ subunit from the inner medulla and up-regulation of NKCC2 suggests that altered renal Na⁺ handling is also programmed prenatally.