Renal Deletion of 12 kDa FK506-Binding Protein Attenuates Tacrolimus-Induced Hypertension

Abstract

Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension. 27: 145627: -146427: , 201627: . doi: 10.1681 Tacrolimus, a widely prescribed calcineurin inhibitor, is an immunosuppressive drug often used to prevent the rejection of transplanted organs. 1 Its use, however, is frequently complicated by side effects, including hypertension, hyperkalemia, and CKD. 2 We reported previously that tacrolimus causes hypertension and increases the abundance of the phosphorylated, active, form of the renal sodium chloride cotransporter (NCC) in mice. We showed that NCC activity is essential for the full development of hypertension, and confirmed that tacrolimus increases the abundance of phosphorylated NCC (pNCC) in humans. 3 The molecular mechanisms, however, remain largely unknown. J Am Soc NephrolTo inhibit calcineurin, a serine/threonine phosphatase, tacrolimus must bind to an endogenous protein, the 12 kDa FK506-binding protein (FKBP12). 4 When this occurs in T cells, cytokine production is inhibited and it results in immunosuppression.

Extracellular K+ rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl−‐dependent and independent mechanisms

“…Similarly, a kidney‐specific deletion of FK506 binding protein, crucial for the effects of tacrolimus on PP3, attenuates tacrolimus‐induced arterial hypertension (Lazelle et al . ). However, in our experiments, inhibition of PP1 and PP3 did not block the [K + ] ex ‐induced dephosphorylation of NCC, suggesting that other signalling cascades are involved.…”

NaCl cotransporter abundance in urinary vesicles is increased by calcineurin inhibitors and predicts thiazide sensitivity

“…In a study using a kidney specific 12 kDa FK506-binding protein, FKBP12, knockout mice, Tac caused hypertension by inhibiting calcineurin directly in DCT cells expressing NCC [22]. Moreover, NCC knockout mice were protected from tacrolimus-induced hypertension [21], confirming the role of NCC in CNI-induced hypertension.…”

Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport

“…First, although the Pax8 system is relatively specific for kidney epithelia, 34,35 substantial gene deletion also occurs in the liver, which may have contributed to extrarenal K + uptake. Second, extrarenal MR may be stimulated in KS MR 2/2 mice at baseline, because plasma [aldosterone] is elevated; the addition of supraphysiologic aldosterone, then, may have little additional effect.…”