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Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.

ABSTRACT: Salt homeostasis is maintained by tight control of Na+ filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na+ channel (ENaC), which is rate-limiting for Na+ reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high dietary Na+ exacerbated kidney injury in Nedd4-2-deficient mice, significantly perturbing normal postnatal nephrogenesis and resulting in multifocal areas of renal dysplasia, increased markers of kidney injury and a decline in renal function. In control mice, high dietary Na+ resulted in reduced levels of ENaC. However, Nedd4-2-deficient kidneys maintained elevated ENaC even after high dietary Na+, suggesting that the inability to efficiently downregulate ENaC is responsible for the salt-sensitivity of disease. Importantly, low dietary Na+ significantly ameliorated nephropathy in Nedd4-2-deficient mice. Our results demonstrate that due to dysregulation of ENaC, kidney injury in Nedd4-2-deficient mice is sensitive to dietary Na+, which may have implications in the management of disease in patients with kidney disease.

SUBMITTER: Manning JA

PROVIDER: S-EPMC7244563 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.

Manning Jantina A JA Shah Sonia S SS Henshall Tanya L TL Nikolic Andrej A Finnie John J Kumar Sharad S

Cell death and differentiation 20191204 6

Salt homeostasis is maintained by tight control of Na+ filtration and reabsorption. In the distal part of the nephron the ubiquitin protein ligase Nedd4-2 regulates membrane abundance and thus activity of the epithelial Na+ channel (ENaC), which is rate-limiting for Na+ reabsorption. Nedd4-2 deficiency in mouse results in elevated ENaC and nephropathy, however the contribution of dietary salt to this has not been characterized. In this study we show that high die ...[more]

PMID: 31802037

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Project description:A mouse model of chylomicron deficiency was recently developed; these mice express a human apolipoprotein (apo) B transgene in the liver but do not synthesize any apoB in the intestine. Despite severe intestinal fat malabsorption, the mice maintain normal concentrations of plasma lipids and liver-derived apoB 100-containing lipoproteins. We investigated the metabolic mechanisms by which plasma lipid levels are kept normal. De novo lipogenesis (DNL) and cholesterogenesis were measured by mass isotopomer distribution analysis (MIDA). Plasma non-esterified fatty acid (NEFA) fluxes and hepatic re-esterification of labelled plasma NEFA were also measured. Hepatic and plasma triacylglycerol (TG) concentrations and plasma NEFA fluxes were not different between chylomicron-deficient mice and controls. The contribution from DNL to the hepatic TG pool was only modestly higher in chylomicron-deficient mice [12+/-2.1% (n=7) compared with 3.7+/-1.0% (n=9); means+/-S.E.M.], whereas cholesterogenesis was markedly elevated. The fractional contribution from plasma NEFA to hepatic TG was greatly elevated in the chylomicron-deficient animals (62% compared with 23%). Accordingly, 73% of hepatic TG was neither from DNL nor from plasma NEFA in controls, presumably reflecting prior contribution from chylomicron remnants, compared with only 26% in the chylomicron-deficient group. The long-term contribution from DNL to adipose fat stores reached approximately the same steady-state values (approximately 30%) in the two groups. Body fat accumulation was much lower in chylomicron-deficient animals; thus, whole-body absolute DNL was significantly lower. We conclude that plasma and hepatic TG pools and hepatic secretion of apoB-containing particles are maintained at normal levels in chylomicron-deficient mice, not by de novo fatty acid synthesis, but by more avid re-esterification of plasma NEFA, replacing the normally predominant contribution from chylomicrons, and that some dietary fat can be absorbed by apoB-independent mechanisms.

Dataset Information

Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.

Publications

Dietary sodium modulates nephropathy in Nedd4-2-deficient mice.

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