Metabolic syndrome patients have
insulin resistance, which causes
hyperinsulinemia, which in turn causes aberrant increased renal
sodium reabsorption. The precise mechanisms underlying this greater
salt sensitivity of hyperinsulinemic patients remain unclear. Abnormal activation of the recently identified with-no-
lysine kinase (WNK)-oxidative stress-responsive
kinase 1 (OSR1)/STE20/SPS1-related
proline/
alanine-rich
kinase (SPAK)-NaCl cotransporter (NCC) phosphorylation cascade results in the
salt-sensitive
hypertension of
pseudohypoaldosteronism type II. Here, we report a study of renal WNK-OSR1/SPAK-NCC cascade activation in the db/db mouse model of hyperinsulinemic
metabolic syndrome.
Thiazide sensitivity was increased, suggesting greater activity of NCC in db/db mice. In fact, increased phosphorylation of OSR1/SPAK and NCC was observed. In both SpakT243A/+ and Osr1T185A/+ knock-in db/db mice, which carry mutations that disrupt the signal from WNK
kinases, increased phosphorylation of NCC and elevated blood pressure were completely corrected, indicating that phosphorylation of SPAK and OSR1 by WNK
kinases is required for the increased activation and phosphorylation of NCC in this model. Renal phosphorylated Akt was increased in db/db mice, suggesting that increased NCC phosphorylation is regulated by the
phosphatidylinositol 3-kinase/Akt signaling cascade in the kidney in response to
hyperinsulinemia. A
phosphatidylinositol 3-kinase inhibitor (NVP-BEZ235) corrected the increased OSR1/SPAK-NCC phosphorylation. Another more specific
phosphatidylinositol 3-kinase inhibitor (GDC-0941) and an Akt inhibitor (MK-2206) also inhibited increased NCC phosphorylation. These results indicate that the
phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in db/db mice. This mechanism may play a role in the pathogenesis of
salt-sensitive
hypertension in human hyperinsulinemic conditions, such as the
metabolic syndrome.