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, 0.01 and 0.001 µM significantly stimulated ET-1 secretion by cultured tubular and mesangial cells. CyA at 10, 1, 0.1 and 0.01 µM also exerted an enhancing effect on ET-1 secretion in cultured tubular cells whereas CyA only at 10 and 1 µM had a stimulatory effect on ET-1 secretion by human mesangial cells. We observed that the concentrations of CyA 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-β-D-glucosaminidase (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 CyA.