Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow

Background Cyclosporine A (CsA)-induced chronic nephrotoxicity is character ized by interstitial fibrosis and afferent arteriole hyalinosis. CsA lesion has been linked to maintained renal vasoconstriction and narrowing of the afferent arteriole lumen diameter, leading to preglomerular ischemia. We in vestigated the role of renal hemodynamics in CsA-induced transforming growt h factor (TGF-beta) expression and interstitial fibrosis. Methods. Groups of rats fed a low salt diet were given CsA 5 mg/kg/day (CsA ) or the vehicle (olive oil, [VH]) s.c. and had the renal blood flow (RBF), glomerular filtration rate (GFR), mean arterial pressure, renal vascular r esistance, renal histologic changes, and immunohistochemical features for m acrophages and TGF-beta evaluated after 1, 2, and 8 weeks of treatment. Results. At week. 1, despite normal renal hemodynamics and MAP, there was a significant macrophage interstitial influx in CsA-treated rats (70+/-16 vs . 29+/-4 cells+/-0.5 mm(2), in CsA vs. VH, P=0.02) that was progressive wit h treatment (80+/-13 vs. 32+/-8 cells+/0.5 mm(2), P=0.016 and 197+/-36 vs. 23+/-3 cells+/0.5 mm(2), P=0.0002, CsA vs. VH at 2 and 8 weeks, respectivel y), After 2 weeks of treatment, CsA animals developed a significant interst itial fibrosis, with preserved RBF, even when it was assessed 2 hr after Cs A injection. There was a significant increase in the immunostaining for TGF -beta in the juxtaglomerular arterioles in CsA-treated rats (48.6+/-3.8 vs. 35.1+/-1.1%, CsA vs. VH at 2 weeks, P<0.05 and 59.0+/-3.2 vs. 37.0+/-2.1%, CsA vs. VH at 8 weeks, P=0.0001). A significant and progressive GFR decrea se followed the renal structural injury of CsA treatment. Arteriolar and gl omerular anatomic injury were not found throughout the study. Conclusions. Low CsA doses might generate interstitial fibrosis without any decrease in RBF or structural arteriolar lesion evidence, possibly through early macrophage influx and increased TGF-beta expression. It clearly seem s that CsA-induced ischemia and tubulointerstitial injury may occur indepen dently, suggesting that chronic CsA nephrotoxicity may be very hard to prev ent or even not be preventable at all.