Role of Intrarenal Endothelin 1, Endothelin 3, and Angiotensin II Expression in Chronic Cyclosporin A Nephrotoxicity in Rats

Abstract

Endothelin 1 (Et1) is widely expressed in the kidney and is related to several functions and to pathological conditions with progression towards sclerosis. The function of endothelin 3 (Et3) at the renal level is debatable, but it could have an important regulatory function in the reabsorption of water through its action on tubular type B receptors. Angiotensin II has recently been implicated as the principal factor responsible for the progression of interstitial fibrosis induced by cyclosporin A (CsA). We investigated this relationship in vivo and analyzed the modifications induced by CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day of CsA for 28 and 56 days. Immunohistochemical methods and molecular analysis were used to study the expression of Et1 and Et3 and immunohistochemistry alone to determine the intrarenal expression of angiotensin II. Rats treated with CsA developed chronic nephrotoxicity lesions; semiquantitative analyses of hyaline arteriolopathy revealed that the passage of time affected the extent of this lesion and led to the diminution of the total glomerular area. Immunohistochemical results showed that chronic CsA treatment induced moderate secretion of Et1 and Et3 at tubular and glomerular levels and that the local expression of angiotensin II in the treatment groups was more evident than in control animals. Besides, the mRNA levels of preproEt3 showed a dramatic increase from 28 days after CsA treatment (control group 0.07 ± 0.11 vs. CsA group 0.48 ± 0.11, p < 0.01), while the mRNA levels of preproEt1 increased from 56 days (control group 0.15 ± 0.05 vs. CsA group 0.34 ± 0.09, p < 0.05). At 28 days, renal lesions correlated strongly with the mRNA levels of Et3 (r > 0.50, p < 0.01). However, at 56 days, the key finding was the strong correlation of the most important analytical, histological, and immunohistochemical parameters of CsA nephrotoxicity with Et1 mRNA levels (r > 0.50, p < 0.01). These results support the hypothesis that the clinical and morphological phenomena linked with CsA nephrotoxicity are related to hypersecretion of endothelins and local expression of angiotensin II in the outer medulla and medullary rays; Et3 and angiotensin II are the first to act, followed subsequently by Et1.

Effect of acute and chronic treatment of Cyclosporin A on liver and kidney functions in rats

“…Several mechanisms have been proposed in cyclosporineinduced nephrotoxicity, namely, the activation of the reninangiotensin system and enhanced sympathetic tone (Dell et al, 2003), increased synthesis of endothelin (Ramirez et al, 2000), inductions of cytochrome P450 enzymes in renal microsomes (Serino et al, 1994), and renal vasoconstriction attributed to an imbalance in releasing of the vasoactive substances, including reduction of vasodilator factors in particular nitric oxide (Yoon et al, 2009). Other studies have clearly demonstrated that cyclosporine-induced oxidative stress plays a pivotal role in producing structural and functional impairment of the kidney (Burdmann et al, 2003).…”

Risk Factors for Cyclosporin A Nephrotoxicity in Children with Steroid-Dependant Nephrotic Syndrome

“…Recent clinical studies in elderly patients with atherosclerotic vascular disease suggested, in fact, that excessive angiotensin II inhibition in kidneys that are vascularly compromised may have detrimental effects (33). Conversely, experimental models of CsA-induced interstitial fibrosis have shown that CsA renal toxic effects are mediated in part by angiotensin II and that, despite more pronounced renal hypoperfusion, the addition of an ACEI to CsA limits tubulointerstitial changes (34,35).…”

The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease

“…Immunohistochemical studies of a model of chronic cyclosporin A toxicity in rats revealed intrarenal deposits of Ang II, which increased with time (del Moral et al, 1997). Increased expression of Ang II was observed in the outer medulla and medullary rays in rats treated with cyclosporin A (Ramírez et al, 2000).…”