High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment

Ruta LM, Dickinson H, Thomas MC, Denton KM, Anderson WP, Kett MM. High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment. Am J Physiol Renal Physiol 298: F1384-F1392, 2010. First published March 24, 2010; doi: 10.1152/ajprenal.00049.2010.-The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the "first hit" and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24-h MAP was not different between WT, HET2K, and HET1K mice (102 +/- 1, 103 +/- 1, and 102 +/- 2 mmHg). On a high-salt diet, MAP increased 9.1 +/- 1.9 mmHg in HET1K mice (P < 0.05) and 5.4 +/- 0.9 mmHg in HET2K mice (P < 0.05) and did not change significantly in WT mice. Creatinine clearance was 60% higher in WT mice but 30% lower in HET2K and HET1K mice fed a high-salt diet than in controls maintained on a normal-salt diet. Thus a reduction in nephron number (or total glomerular volume) alone does not lead to hypertension or kidney disease in aged mice, but exposure to high salt uncovers a hypertensive and renal phenotype.