FK506 mechanism of nephrotoxicity: stimulatory effect on endothelin secretion by cultured kidney cells

Abstract

The administration of FK506 or cyclosporin A (CyA) to animals and humans induces a decrease in glomerular filtration rate and renal plasma flow and an increase in renal vascular resistance. Endothelins (ET-1), very powerful renal vasoconstrictors, are involved in CyA-related alteration in renal haemodynamics. In this study we sought to determine whether FK506 and CyA had a stimulatory effect on endothelin secretion by cultured kidney cells (tubular and mesangial cells) and whether this stimulatory effect coincided with an increase in ET-1 serum level in FK506-and CyA-treated rats. FK506 concentrations of 1, 0.1, O.Ql and 0.001j.tM significantly stimulated ET-1 secretion by cultured tubular and mesangial cells. CyA at 10, 1, 0.1 and 0.01j.tM also exerted an enhancing effect on ET-1 secretion in cultured tubular cells whereas CyA only at 10 and lj.tM had a stimulatory effect on ET-1 secretion by human mesangial cells. We observed that the concentrations of Cy A that induced the most substantial enhancing effect were 10 or 100 times higher than those required for FK506 to produce the same effect. The concentrations of FK506 or CyA which induced ET-1 secretion by tubular cells and kidney cells were not cytolytic as assessed by N-acetyl-~-D-glucos aminidase (NAG) release and lactic dehydrogenase (LDH) release. FK506 or CyA treatment at toxic doses induced an increase in serum level of ET-1 in treated rats. We conclude that FK506 and CyA induced an increase in the synthesis of endothelin in the kidney which may explain the increase in circulating ET-1. This stimulatory effect may contribute to the genesis of haemodynamic preturbations associated with FK506 and Cy A. FK506 is a newly developed immunosuppressive drug which has been used successfully in clinical transplanta-Offprint requests to: Michio Ishibashi. M.D.tion [4,13]. Among its recognized side effects, nephrotoxicity is the most prominent [3]. Its molecular structure is unrelated to cyclosporin A (CyA), but both agents have similar pharmacological effects and may possibly have the same toxicity. It has been reported that FK506 decreases the glomerular filtration rate (GFR) and renal plasma flow (RFP) and increases renal vascular resistance in humans [19] and in rats [7] treated with FK506. These reversible haemodynamic perturbations that have also been observed in CyA nephrotoxicity, have been linked to the renin angiotensin, adrenergic systems, and thromboxane A2 [8,11]. Endothelin (ET), a peptide isolated from supernatants of cultured porcine aortic endothelial cells is a very powerful renal vasoconstrictor [20]. ET is ten times more potent than angiotensin II, vasopressin, or neuropeptide Y, making it the most potent endogenous vasoacth:e substance known [20]. ET appears to have a pivotal role in the pathophysiology of Cy A-induced acute renal vasoconstriction and glomerular dysfunction [5]. Renal cell lines and mesangial cells physiologically express mRNA for endothelin and secrete this peptide in the supernatant [14,21]. In this study we demonstrated that...

Mechanisms of FK 506–Induced Hypertension in the Rat

“…We have reported that FK 506 increased the production of ET-1 and the levels of ET-1 mRNA in human vascular endothelial cells. 10 Moutabarrik et al 34 also reported that FK 506 increased the secretion of ET-1 from cultured kidney cells and that oral administration of FK 506 elevated plasma ET-1 concentrations. The synthesis of bioactive ET-1 requires a recently cloned phosphoramidon-sensitive ECE.…”

Increased Excretion of Urinary 20-HETE in Rats With Cyclosporine-Induced Nephrotoxicity

“…CsA also stimulates the release of endothelin-1 (ET-1) from endothelial, tubular, and mesangial cells (4,5) in rats and has been associated with increased expression of angiotensin II (ANG II) type I receptors in the kidney. Activation of each of these pathways could promote an increase in renal vascular tone.…”

Maternal hemodynamics and pregnancy outcome in women with prior orthotopic liver transplantation

“…The high rate of pregnancy complications is not surprising given that cyclosporine and FK506 cause hypertension and renal insufficiency. [8][9][10][11][19][20][21][22][23][24][25][26][27][28][29][30][31][32] These agents cause systemic and afferent arteriolar vasoconstriction by increasing the production of endothelin and thromboxane A 2 and interfering with nitric oxide-mediated vasodilation. [19][20][21][22][23] The afferent arteriolar vasoconstriction results in significant reductions in glomerular filtration rate and renal blood flow.…”

“…[23][24][25][26] Chronic nephropathy also contributes to the renal insufficiency and is characterized by arteriolar hyalinosis, global glomerulosclerosis, proximal tubule damage, and tubulointerstitial fibrosis. [25][26][27][28][29][30] This report describes the hemodynamics and pregnancy outcomes after orthotopic liver transplantation at our institution. Subjects 2 (during her second pregnancy), 3, 4, and 5 all had abnormally elevated CO during the first or early second trimesters.…”