Jensen, Barbara Ann; (2018) The effects of calcineurin inhibitors on epithelial electrolyte transport. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Calcineurin inhibitor (CNI)-induced hypertension is common after renal transplantation, rendering patients susceptible to cardiovascular and kidney disease, graft failure and death. CNI-induced hypertension occurs as a result of enhanced sodium retention by activation, via phosphorylation, of the renal thiazide-sensitive NaCl cotransporter, NCC (SLC12A3). CNI-treated renal transplant patients also have increased NCC abundance in isolated urinary exosomes. The studies described in this thesis were designed to investigate the effects of CNI treatment on mouse renal and intestinal sodium transport proteins, to determine whether alterations in proteins other than NCC may also contribute towards sodium retention. These changes were compared with those in an established mouse model of metabolic syndrome, comprising hypertension, insulin resistance, obesity and hypercholesterolemia which are also associated with CNI use. The abundance of NCC and phospho-NCC was also investigated in urinary exosomes from patients taking CNIs or with Gitelman syndrome. There was a higher abundance of NCC and pNCC in urinary exosomes from CNI-treated renal transplant patients compared with patients with Gitelman syndrome. Both CNI-treated and metabolic syndrome rodent models displayed a significant increase in pNCC. No differences were observed for intestinal transport proteins with CNI-treatment, however, a lower abundance of PiT1 and SGLT1 in the small intestine was observed with high-fat feeding. Renal NHE3 and ENaC were down-regulated in CNI-treated mice, a response that could be compensatory to the upregulation of pNCC in the DCT. These data provide evidence that CNIs influence a number of renal sodium transport proteins that may contribute towards the development of hypertension following transplantation. These studies suggest an important role for calcineurin in the regulation of blood pressure and sodium transport in the kidney, and its possible involvement in the pathogenesis of hypertension and electrolyte disorders.

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