Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats

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 three 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 KIM-1 (fold change, FC 3.4; p=0.003), 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 to baseline. Nifedipine treatment reduced blood pressure 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 between salt, UMOD, and blood pressure. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.

Favorable Effects of Virgin Coconut Oil on Neuronal Damage and Mortality after a Stroke Incidence in the Stroke-Prone Spontaneously Hypertensive Rat

“…On the other hand, protective effects on the kidneys may also have been conferred by VCO since the salt-loaded water may have also produced an effect in the kidney. This is different from the study of Mary et al [49] who reported that there were no deleterious effects on the kidneys after 3 weeks of 1% salt-loading in SHRSPs. However, since the experiment in the current study was performed for 10 weeks, with the first death occurring at 4 weeks after the start of the salt loading, the differences in the lengths of the experiments might be attributed to the possible differences in the kidney.…”

Uromodulin biology

“…As summarized above, salt loading triggered uromodulin accumulation in TAL cells from hepsin-deficient mice [ 36 ]. These results are in line with two studies in rats, in which salt loading increased uromodulin kidney mRNA and medullary protein in normotensive Sprague–Dawley rats [ 102 ] and intracellular uromodulin retention in hypertensive [stroke-prone spontaneously hypertensive rat (SHRSP)] and normotensive rats (Wistar–Kyoto) [ 103 ]. In the latter study, 24-h uUMOD excretion was studied and decreased upon salt loading in both rat strains [ 103 ].…”

Uromodulin: more than a marker for chronic kidney disease progression

“…Similarly, the vasopressin analog desmopressin has been shown to increase uUMOD secretion in one study [21 ▪ ] while decreasing its secretion rate in another [8]. In the more recent study [21 ▪ ], vasopressin was found to induce a short-term increase in urinary secretion that was dependent on the protein kinase A signaling pathway that also resulted in an overall decrease in kidney levels of uromodulin. Using polarized tubular epithelial cells, the authors found that this regulation only occurred with the apical (urinary) form and not the basolateral (circulating) form.…”

“…Although water loading increases secretion of uUMOD [15–17], the effect of salt intake is debated, with some studies finding increased secretion [18,19] and others finding decreased secretion [20]. Similarly, the vasopressin analog desmopressin has been shown to increase uUMOD secretion in one study [21 ▪ ] while decreasing its secretion rate in another [8]. In the more recent study [21 ▪ ], vasopressin was found to induce a short-term increase in urinary secretion that was dependent on the protein kinase A signaling pathway that also resulted in an overall decrease in kidney levels of uromodulin.…”