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 SPAK and OSR1. Here, we show that a kidney-specific SPAK isoform, which lacks the kinase domain, inhibits phosphorylation of NCC and NKCC2 by full-length SPAK in vitro.

Overexpression of the sodium chloride cotransporter is not sufficient to cause familial hyperkalemic hypertension.

The sodium chloride cotransporter (NCC) is the primary target of thiazides diuretics, drugs used commonly for long-term hypertension therapy. Thiazides also completely reverse the signs of familial hyperkalemic hypertension (FHHt), suggesting that the primary defect in FHHt is increased NCC activity. To test whether increased NCC abundance alone is sufficient to generate the FHHt phenotype, we generated NCC transgenic mice; surprisingly, these mice did not display an FHHt-like phenotype.

The WNK kinase network regulating sodium, potassium, and blood pressure.

The relationship between renal salt handling and hypertension is intertwined historically. The discovery of WNK kinases (With No lysine = K) now offers new insight to this relationship because WNKs are a crucial molecular pathway connecting hormones such as angiotensin II and aldosterone to renal sodium and potassium transport. To fulfill this task, the WNKs also interact with other important kinases, including serum and glucocorticoid-regulated kinase 1, STE20/SPS1-related, proline alanine-rich kinase, and oxidative stress responsive protein type 1.