PKC-α contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2.High NaCl in the renal medullary interstitial fluid powers the concentration of urine but can damage cells.  We studied whether PKC-α contributes to the activation of NFAT5.  PKC-α protein abundance was greater in the renal medulla than in the cortex.  Knockout of PKC-α reduced NFAT5 protein abundance and expression of its target genes in the inner medulla.  In human embryonic kidney (HEK)-293 cells, high NaCl increased PKC-α activity, and small interfering RNA-mediated knockdown of PKC-α attenuated high NaCl-induced NFAT5 transcriptional activity.  Knockout of PKC-α decreased ERK1/2 phosphorylation in the inner medulla, as did knockdown of PKC-α in HEK-293 cells.  Combined knockdown of PKC-α and ERK2 had no greater effect than knockdown of either alone.  Knockdown of either PKC-α or ERK2 reduced the high NaCl-induced increase of NFAT5 transactivating activity.  PKC-α has been previously shown to increase SHP-1-S591-P, which raised the possibility that PKC-α might be acting through SHP-1.  However, we did not find that knockout of PKC-α in the renal medulla or knockdown in HEK-293 cells affected SHP-1-S591-P.  We conclude that PKC-α contributes to high NaCl-dependent activation of NFAT5 through ERK1/2 but not through SHP-1-S591.
PKC
PKC-α contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2.High NaCl in the renal medullary interstitial fluid powers the concentration of urine but can damage cells. 
MAPK ERK1/2
PKC-α contributes to high NaCl-induced activation of NFAT5 (TonEBP/OREBP) through MAPK ERK1/2.High NaCl in the renal medullary interstitial fluid powers the concentration of urine but can damage cells. 
NFAT5 (TonEBP/OREBP)
We have previously found that the high NaCl-induced increase of phosphorylation of Ser(591) on Src homology 2 domain-containing phosphatase 1 (SHP-1-S591-P) contributes to the activation of NFAT5 in cell culture, and here we found high levels of SHP-1-S591-P in the inner medulla.  PKC-α has been previously shown to increase SHP-1-S591-P, which raised the possibility that PKC-α might be acting through SHP-1.  However, we did not find that knockout of PKC-α in the renal medulla or knockdown in HEK-293 cells affected SHP-1-S591-P. 
SHP-1-S591-P