TNF-UMOD interactions and susceptibility to salt-induced hypertension

New York Medical College, Valhalla NY

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Abstract

The DASH2 study was a multicenter randomized trial in which the effects on blood pressure of three levels of sodium intake were evaluated in two diets among adults whose blood pressure exceeded 120/80 mm Hg, including those with stage 1 hypertension (a systolic blood pressure of 140 to 159 mm Hg or a diastolic blood pressure of 90 to 95 mm Hg). Despite limitations related to the applicability of the DASH diet to all populations, this diet was shown to substantially lower blood pressure both in people with and without hypertension when compared with a typical diet in the United States. The DASH diet has been recommended in national guidelines regarding sodium intake and blood pressure and the findings are consistent with other clinical trials showing that reducing the sodium chloride content of typical diets in the United States or northern Europe lowers blood pressure. We recently showed that tumor necrosis factor-alpha (TNF) production by the thick ascending limb of Henle's loop (TAL) is activated by increases in sodium chloride intake. Moreover, TNF production induced by dietary salt ingestion was exclusively observed in the urine, as plasma levels remained unchanged. The effects of TNF on TAL cell function were evaluated in experiments performed using precision tools we developed to target TNF in this segment of the nephron, namely TAL-specific TNF deficient mice and intrarenal administration of TAL-specific shRNA lentivirus to silence TNF. Use of these complementary approaches revealed that TNF production by the TAL in response to high salt intake serves as a negative feedback mechanism that attenuates Na+-K+-2Cl- cotransporter (NKCC2) expression and activity, thereby contributing to the maintenance of blood pressure by limiting increases in NaCl reabsorption. Since subjects in DASH2 were fed three sodium levels using a randomly assigned crossover design, we will determine how the relationship between urinary levels of TNF and blood pressure relates to sodium intake in subjects ingesting either the control or DASH diet. For instance, the effects of sodium within the diets will be assessed by comparing the decrease in blood pressure from the high to the intermediate level of sodium with the decrease from the intermediate to the low level of sodium. Analyses will include assessments of urinary TNF and uromodulin (UMOD) levels, the latter being part of a mechanism that regulates TNF function. Selected UMOD single nucleotide polymorphism (SNP) profiles also will be constructed according to gender, race, and sodium intake in the context of interventions defined by the DASH2 study. The maintenance of sodium homeostasis is essential for the regulation of blood pressure and insights regarding novel mechanisms that regulate renal sodium excretion may provide new information related to the onset and maintenance of hypertension.