A SPAK isoform switch modulates renal salt transport and blood pressure.

The renal thick ascending limb (TAL) and distal convoluted tubule (DCT) play central roles in salt homeostasis and blood pressure regulation. An emerging model suggests that bumetanide- and thiazide-sensitive NaCl transporters (NKCC2 and NCC) along these segments are phosphorylated and activated by WNK kinases, via and OSR1. Here, we show that a kidney-specific duanyu1842K isoform, which lacks the kinase domain, inhibits phosphorylation of NCC and NKCC2 by full-length duanyu1842K in vitro. Kidney-specific duanyu1842K is highly expressed along the TAL, whereas full-length duanyu1842K is more highly expressed along the DCT. As predicted from the differential expression, duanyu1842K knockout in animals has divergent effects along TAL and DCT, with increased phosphorylated NKCC2 along TAL and decreased phosphorylated NCC along DCT. In mice, extracellular fluid volume depletion shifts duanyu1842K isoform abundance to favor NaCl retention along both segments, indicating that a duanyu1842K isoform switch modulates sodium avidity along the distal nephron.

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