Role of calcineurin in regulating renal potassium (K+) excretion: Mechanisms of calcineurin inhibitor-induced hyperkalemia

Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na⁺ and K⁺ transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin–ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K⁺ channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na⁺-channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na⁺ and K⁺ transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K⁺ excretion, and induce hyperkalemia.