High nephron endowment protects against salt-induced hypertension

Abstract

Walker KA, Cai X, Caruana G, Thomas MC, Bertram JF, Kett MM. High nephron endowment protects against salt-induced hypertension. Am J Physiol Renal Physiol 303: F253-F258, 2012. First published May 9, 2012 doi:10.1152/ajprenal.00028.2012.-While low nephron number is associated with increased risk of developing cardiovascular and renal disease, the functional consequences of a high nephron number are unknown. We tested the hypothesis that a high nephron number provides protection against hypertensive and renal insults. Mean arterial pressure (MAP) and renal function were characterized in male wild-type (WT) and transforming growth factor-␤2 heterozygous (Tgfb2 ϩ/Ϫ ) mice under basal conditions and following a chronic high-salt diet. Kidneys were collected for unbiased stereological analysis. Baseline MAP and renal function were indistinguishable between genotypes. The chronic high-salt diet (5% NaCl for 4 wk followed by 8% NaCl for 4 wk) led to similar step-wise increases in urine volume, Na ϩ excretion, and albuminuria in the genotypes. The 5% NaCl diet induced modest and similar increases in MAP (3.5 Ϯ 1.6 and 3.4 Ϯ 0.8 mmHg in WT and Tgfb2 ϩ/Ϫ , respectively). After the step up to the 8% NaCl diet, MAP increased further in WT (ϩ15.9 Ϯ 5.1 mmHg), but not Tgfb2 ϩ/Ϫ (Ϫ0.1 Ϯ 1.0 mmHg), mice. Nephron number was 30% greater in Tgfb2 ϩ/Ϫ than WT mice and was not affected by the chronic high-salt diet. Mean glomerular volume was lower in Tgfb2 ϩ/Ϫ than WT mice, and the chronic high-salt diet induced significant glomerular hypertrophy. In a separate cohort of mice, an acute, 7-day, 8% NaCl diet induced similar rises in MAP in the genotypes. This is the first study to examine the physiological characteristics of a model of high nephron number, and the findings are consistent with this phenotype providing protection against chronic, but not acute, hypertensive insults. renal stereology; renal function; mean arterial pressure

Maternal Fat Feeding Augments Offspring Nephron Endowment in Mice

“…Heterozygous null TGF-β2 mice show a 30–60% increase in nephron endowment but normal urine osmolality, albumin excretion, creatinine clearance and blood pressure at 4–6 months of age [55, 56]. As mentioned previously, Boubred et al [37] reported a 20% increase in nephron endowment in rats exposed to early postnatal hypernutrition.…”

“…A high nephron endowment may also have a protective effect on renal function and glomerular morphology, as shown in heterozygous TGF-β2 mice following a chronic insult [55]. Exposure to a high salt diet raised mean arterial pressure in wild type mice, but not heterozygous TGF-β2 mice.…”

Development of the Mammalian Kidney

“…Surprisingly, nephron number appears even more variable in man: reports suggest as much as a ten fold difference in nephron number amongst individuals with around 1,000,000 nephrons on average per kidney (Bertram et al, 2011). This large difference may not be trivial as studies link low nephron number to an elevated risk of kidney disease while higher nephron content in the mouse protects against salt-induced hypertension (Hoy et al, 2011; Walker et al, 2012). …”

Factors associated with a vicious cycle involving a low nephron number, hypertension and chronic kidney disease

“…Cullen-McEwen et al 78 reported an elevated arterial pressure and glomerular hypertrophy in aged GDNF heterozygous mice. Moreover, Walker et al 79 showed that an augmented nephron endowment in transforming growth factor-β2 heterozygous (Tgfb2 (+/ − )) mice protects against the hypertensive effects of a chronic high-salt diet. This finding is consistent with the hypothesis that the Meanwhile, several animal studies have suggested that even marked nephron deficiency and hyperfiltration do not always lead to HTN or renal dysfunction.…”