TY - JOUR
T1 - Cyclosporine metabolic side effects
T2 - Association with the WNK4 system
AU - Melnikov, Semyon
AU - Mayan, Haim
AU - Uchida, Shinichi
AU - Holtzman, Eliezer J.
AU - Farfel, Zvi
PY - 2011/10
Y1 - 2011/10
N2 - Background Cyclosporine is used for treatment of transplanted patients and for immune-mediated diseases. Cyclosporine is known to cause a combination of metabolic side effects including hypertension, hyperkalemia, hypercalciuria and hypomagnesemia. These side effects except for hypomagnesemia are the cardinal features of familial hyperkalemia and hypertension (FHHt), also called pseudohypoaldosteronism type II (PHA II). FHHt is caused by mutations in the kinases WNK1 and WNK4 resulting in an increase in renal Na-Cl cotransporter (NCC) apical distribution and function. Therefore, we studied whether cyclosporine's metabolic side effects are mediated by WNK4 and NCC. Design Sprague-Dawley (SD) rats were treated by cyclosporine 25mgkg -1 subcutaneously for 14days. Blood pressure, blood chemistry values and kidney WNK4 protein were determined. In addition, mDCT cells were exposed to cyclosporine, and their WNK4 mRNA and protein content, and their NCC protein content and phosphorylation were determined. Results The rats developed an FHHt-like syndrome including hypertension, hyperkalemia and salt-sensitive hypercalciuria. A significant increase in their kidney WNK4 protein content (0·13±0·01 vs. 0·67±0·16 WNK4/GAPDH in controls, P=0·0183) was found. In mDCT cells, cyclosporine caused a rise in WNK4 mRNA levels and also a threefold rise in WNK4 protein content. This rise was followed by a rise in NCC protein content and pSer71 phosphorylation. Conclusions These observations may explain in part the mechanism of cyclosporine-induced hypertension, hyperkalemia and hypercalciuria.
AB - Background Cyclosporine is used for treatment of transplanted patients and for immune-mediated diseases. Cyclosporine is known to cause a combination of metabolic side effects including hypertension, hyperkalemia, hypercalciuria and hypomagnesemia. These side effects except for hypomagnesemia are the cardinal features of familial hyperkalemia and hypertension (FHHt), also called pseudohypoaldosteronism type II (PHA II). FHHt is caused by mutations in the kinases WNK1 and WNK4 resulting in an increase in renal Na-Cl cotransporter (NCC) apical distribution and function. Therefore, we studied whether cyclosporine's metabolic side effects are mediated by WNK4 and NCC. Design Sprague-Dawley (SD) rats were treated by cyclosporine 25mgkg -1 subcutaneously for 14days. Blood pressure, blood chemistry values and kidney WNK4 protein were determined. In addition, mDCT cells were exposed to cyclosporine, and their WNK4 mRNA and protein content, and their NCC protein content and phosphorylation were determined. Results The rats developed an FHHt-like syndrome including hypertension, hyperkalemia and salt-sensitive hypercalciuria. A significant increase in their kidney WNK4 protein content (0·13±0·01 vs. 0·67±0·16 WNK4/GAPDH in controls, P=0·0183) was found. In mDCT cells, cyclosporine caused a rise in WNK4 mRNA levels and also a threefold rise in WNK4 protein content. This rise was followed by a rise in NCC protein content and pSer71 phosphorylation. Conclusions These observations may explain in part the mechanism of cyclosporine-induced hypertension, hyperkalemia and hypercalciuria.
KW - Cyclosporine
KW - Familial hyperkalemia and hypertension (FHHt)
KW - Hypercalciuria
KW - Na-Cl cotransporter (NCC)
KW - WNK4 kinase
UR - http://www.scopus.com/inward/record.url?scp=80052633099&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2362.2011.02517.x
DO - 10.1111/j.1365-2362.2011.02517.x
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AN - SCOPUS:80052633099
SN - 0014-2972
VL - 41
SP - 1113
EP - 1120
JO - European Journal of Clinical Investigation
JF - European Journal of Clinical Investigation
IS - 10
ER -