Leung, King Yan Felice; (2017) The Effect of Calcineurin Inhibition on the Expression and Activation of Renal Electrolyte Transporters. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tacrolimus (FK506) is a calcineurin inhibitor (CNI), and the main immunosuppressant used in organ transplantation. It causes complications such as hypertension, hyperkalaemia, hypercalciuria and acidosis. Together with insulin resistance, dyslipidaemia and obesity, they comprise the metabolic syndrome. CNIs induce hypertension through the activation of the WNK-NCC cascade, causing an increase in sodium chloride reabsorption, and phosphorylation is an important post-translational modification that alters the activity of the members in the WNK-NCC cascade. Using quantitative phosphoproteomics and several bioinformatic techniques, a phosphoproteome profile of the renal cortices from FK506-treated mice was generated and phosphoproteins involved in renal tubular transport were identified. In this data, AKT was phosphorylated by FK506 and was suggested to act as the intermediary protein in the calcineurin-WNK cascade. In addition, ERK1/2 was also dysregulated by FK506 and was suggested to regulate NCC through the WNK4-ERK1/2 pathway. The phosphoproteome profile also revealed several FK506-dysregulated phosphoproteins that are involved in sodium, acid-base, glucose and potassium handling. CNIs have been suggested to cause hypercalciuria through a decrease in TRPV5 and calbindin-D28K expression, however, the effect of FK506 on other regulatory and transport proteins involved in calcium handling is unclear. In contrast to previous studies, FK506 did not dysregulate TRPV5 expression, but instead increased the expression of the basolateral calcium transporters, NCX1 and PMCA. Based on these findings, a novel mechanism explaining CNI-induced hypercalciuria, driven by the activation of NCC, is proposed and the relationship between sodium and calcium handling in the DCT is discussed. The effects of calcineurin inhibition on renal electrolyte transporters and their potential regulators induce salt-sensitive hypertension and hypercalciuria. The findings presented in this thesis contribute to the understanding of the underlying mechanism that governs sodium and calcium handling in the DCT and full elucidation of this molecular machinery is of interest and clinical importance.

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