Role of endothelin in cyclosporine-induced glomerular dysfunction

Abstract

Since recent studies indicate that cyclosporine (CsA) disrupts endothelial integrity and that injured endothelial cells release excess endothelin, we examined endothelin's role in acute cyclosporine nephrotoxicity. Following CsA (20 mg/kg i.v.), rabbit anti-porcine endothelin (aE) serum was continuously infused into a first order branch of the main renal artery in Munich-Wistar rats whereupon the hemodynamics of glomeruli not infused with aE as well as those infused with aE within the same kidney were simultaneously assessed by micropuncture techniques. In CsA treated kidneys, in glomeruli not infused with aE, single nephron GFR (SNGFR) and glomerular plasma flow rate (QA) fell profoundly (on average by 42 and 48%, respectively) below the baseline values in association with lower glomerular capillary pressure and elevated afferent arteriolar resistance. By contrast, in glomeruli infused with aE within the same CsA treated kidneys, this vasoconstrictive pattern was markedly attenuated: SNGFR was, on average, only 19% lower than baseline and values for QA as well as other parameters determining glomerular filtration were at or near the levels observed before administration of CsA. In another group of rats (N = 6) an identical dose of CsA was given to measure the circulating level of endothelin. In these CsA treated rats, endothelin level (measured by radioimmunoassay) was elevated at 41.7 +/- 14.7 pg/ml, contrasting the value of less than 2 pg/ml uniformly observed in identically instrumented normal rats not given CsA (N = 5). Thus, cyclosporine is a potential inducer for endothelin release and endothelin appears to have a pivotal role in pathophysiology of cyclosporine-induced acute renal vasoconstriction and glomerular dysfunction.

Comparison of tumour necrosis factor and endothelin-1 between essential and renal hypertensive patients

“…UAE is considered a marker of severity of glomerular injury both in patients with glomerulonephritis as well as in patients with essential hypertension. 31 Because experimental evidence indicates that ET-1 may participate in the genesis of glomerular injury, 11,12 our data raises the possibility that ET-1 may participate in the pathogenesis of renal injury in hypertension. Alternatively, the increased levels of ET-1 may be the expression of end-organ damage rather than its cause.…”

“…Some data also points to a role of ET-1 in the pathogenesis of glomerular injury. 11,12 Nonetheless, data regarding plasma values of ET-1 in hypertensive subjects with both essential hypertension and renal parenchymal diseases, are still conflicting. [13][14][15] It has also been suggested that a potential increase in the expression of pre-pro-endothelin 1 constitutes one of the mechanisms implicated in TNF␣ glomerular haemodynamic effect.…”

Arginine feeding modifies cyclosporine nephrotoxicity in rats.

“…Second, CsA appears to interfere with the compensatory generation of All within the kidney, a response which is required to maintain efferent arteriolar tone and protect glomerular capillary hydrostatic pressure. The notion that CsA nephrotoxicity involves damage to the vascular endothelium has been posed by others (27). Zoja et al (8) reported time-and dose-dependent alterations in bovine endothelial cells exposed to CsA in culture.…”

Epidermal growth factor (EGF) decreased endothelin‐2 (ET‐2) production in human renal adenocarcinoma cells

“…In addition, concerning pathological roles of EGF in the kidney, it was reported that renal prepro-EGF mRNA and urinary EGF secretion were reduced during cysplatin and ischemia-induced acute renal failure~ m rats [29]. Interestingly, ET(s) appeared to be a deleterious mediator in drug-or ischemia-induced renal failures in rats [30,31]. Therefore, the inhibitory mechanism of the ET-2 gene expression by EGF might play a role in the prevention of overproduction of the potentially toxic peptide, ET-2, in the physiological conditions of the kidney.…”