Cyclosporine-induced interstitial fibrosis and arteriolar TGF-beta expression with preserved renal blood flow.
BACKGROUND
Cyclosporine A (CsA)-induced chronic nephrotoxicity is characterized 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 investigated the role of renal hemodynamics in CsA-induced transforming growth 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 resistance, renal histologic changes, and immunohistochemical features for macrophages 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 mm2, in CsA vs. VH, P=0.02) that was progressive with treatment (80+/-13 vs. 32+/-8 cells+/0.5 mm2, P=0.016 and 197+/-36 vs. 23+/-3 cells+/0.5 mm2, P=0.0002, CsA vs. VH at 2 and 8 weeks, respectively). After 2 weeks of treatment, CsA animals developed a significant interstitial fibrosis, with preserved RBF, even when it was assessed 2 hr after CsA 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 decrease followed the renal structural injury of CsA treatment. Arteriolar and glomerular 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 seems that CsA-induced ischemia and tubulointerstitial injury may occur independently, suggesting that chronic CsA nephrotoxicity may be very hard to prevent or even not be preventable at all.
Vieira
J M
JM
Department of Medicine, University of São Paulo Medical School, Brazil.
Noronha
I L
IL
Malheiros
D M
DM
Burdmann
E A
EA
D000818:Animals; D001160:Arterioles / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology*; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine