Abstract
Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending limb (TAL) epithelial cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. We aimed to dissect the role of dietary salt in renal UMOD excretion in normotension and chronic hypertension. Normotensive Wistar–Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) (n=8/sex/strain) were maintained on 1% NaCl for 3 weeks. A subset of salt-loaded SHRSP was treated with nifedipine. Salt-loading in SHRSP increased blood pressure (ΔSBP 35 ± 5 mmHg, P<0.0001) and kidney injury markers such as kidney injury marker-1 (KIM-1; fold change, FC 3.4; P=0.003), neutrophil gelatinase-associated lipocalin (NGAL; FC, 2.0; P=0.012) and proteinuria. After salt-loading there was a reduction in urinary UMOD excretion in WKY and SHRSP by 26 and 55% respectively, compared with baseline. Nifedipine treatment reduced blood pressure (BP) in SHRSP, however, did not prevent salt-induced reduction in urinary UMOD excretion. In all experiments, changes in urinary UMOD excretion were dissociated from kidney UMOD protein and mRNA levels. Colocalization and ex-vivo studies showed that salt-loading increased intracellular UMOD retention in both WKY and SHRSP. Our study provides novel insights into the interplay among salt, UMOD, and BP. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.
Highlights
Uromodulin (UMOD) is the most abundant protein in the urine of healthy individuals
We have recently studied total renal salt handling in response to dietary salt intake in humans [32]; our present study specially dissects the role of UMOD in the thick ascending limb (TAL) in this process
We show for the first time the effect of salt as a modulator of UMOD excretion and expression against two background phenotypes: normotension (WKY) and hypertension (SHRSP)
Summary
Uromodulin (UMOD) is the most abundant protein in the urine of healthy individuals It is secreted by the epithelial cells of the thick ascending limb (TAL) of the loop of Henle in the kidney. Matafora et al have shown that UMOD secretion is greater in salt-sensitive and resistant hypertensive patients compared with healthy individuals and that the levels of UMOD correlate inversely with sodium excretion [6]. In humans, both serum and urinary UMOD excretion have been inversely associated with cardiovascular disease (CVD) and risk of progressive kidney disease [7,8,9]. If taken out of due context, the inverse nature of the association would appear paradoxical, based on findings by Graham et al and Trudu et al [4,5]
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