A network of diuretic resistance

The maintenance of body fluid homeostasis and blood pressure is regulated by the selective excretion and absorption of salt by the kidney. Current treatments for hypertension rely on drugs, such as thiazide diuretics to restore fluid balance; however, diuretic resistance often develops over time. The thiazide-sensitive sodium chloride co-transporter NCC mediates salt reabsorption and is activated by the kinase SPAK. Despite the prominence of NCC in maintaining electrolyte balance, loss of NCC function in patients results in only mild salt wasting, suggesting compensatory mechanisms. Using a systems biology approach to evaluate compensatory responses in SPAK-deficient mice, Richard Grimm and colleagues at University of Maryland School of Medicine, uncovered adaptive renal mechanisms that allow salt reabsorption even in the absence of the critical salt transporter, NCC.  A combination of global transcriptional profiling, cell biological studies, and phenotypic characterization were used to identify an adaptive response-associated gene signature. The compensatory response was mediated by increased apical expression of the sodium-independent chloride/bicarbonate transporter pendrin in pendrin-positive intercalated cells (PP-ICs), distal nephron remodeling via induction of the Notch pathway, and induction of an a-ketoglutarate paracrine signaling system that stimulated salt transport in PP-ICs. The results of this study provide insight into the biological determinants of diuretic efficacy and resistance. In a companion Commentary, Mark Knepper at NHLBI suggests that several of the newly uncovered network elements responsible for renal compensation of diuretic action could be starting points for the development of anti-compensation therapies. The accompanying image shows the differences in pendrin (red) translocation in cells of the connecting tubule of WT (left) and SPAK KO (right) mice. Note the increased apical translocation of pendrin in SPAK-deficient mice.

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