Related Experiment Video
Updated: Jun 3, 2026

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS
Published on: November 8, 2015
Cyclosporine metabolic side effects: association with the WNK4 system
Semyon Melnikov1, Haim Mayan, Shinichi Uchida
1Laboratory of Biochemical Pharmacology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel.
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 25 mg kg(-1) subcutaneously for 14 days. 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.
Related Concept Videos
Pharmacokinetics: Drug–Drug Interactions
Drug toxicity: Idiosyncratic Reactions
Renal Drug Excretion: Overview
A nephron consists of two primary structures: the renal corpuscle and the renal tubule. The renal corpuscle contains the glomerulus, a network of capillaries where the first step of renal excretion, glomerular filtration, occurs. Blood pressure forces water, ions, and small molecules out...
Nephrotic Syndrome I : Introduction
Hypersensitivity Reactions: Cytolytic Reactions
Renal Drug Excretion: Tubular Secretion