Effect of Rosiglitazone (PPAR-үligand) on Cyclosporine – Induced Chronic Nephrotoxicity in Rats. Histological, Immunohistochemical and Biochemical Study

Background: Cyclosporine A (CsA) is the first choice immuno- suppressant used for prevention of allograft rejection. However CsA therapy is associated with nephrotoxicity. Rosiglitazone (RGZ) is used as anti-diabetic drug. It has anti-inflammatory and anti-fibrotic effect in non diabetic renal diseases. Aim of the Work: Of this work was to investigate whether the renal dysfunction and the histological changes induced by CsA in rats could be modified by concomitant administration of RGZ. Materials and Methods: Forty adult male albino rats were classified into 4 equal groups; GI served as control, received saline orally daily. G II received olive oil orally daily (vehicle for CsA). G III was given CsA orally (15 mg /kg/ day). G IV was given RGZ orally (3mg /kg /day) and CsA as in GIII. The period of the study was 28 days. The body weight (B.W) and the systolic blood pressure (SBP) were recorded for each rat. Urine creatinine, blood urea nitrogen (BUN), serum creatinine (SC) and creatinine clearance (CCl) were calculated. Rats were sacrificed and both kidneys were removed; one was processed for detection of malondialdehyde (MDA) and the other was processed to prepare paraffin blocks. Sections were stained with H E, Masson’s Trichome and PAS stains. Other sections were processed for immuno- histochemical demonstration of caspase-3. Results: Revealed a significant increase in SBS, BUN, SC and tissue MDA and significant decrease in BW and CCL of CsA- treated rats (G III). Histological examination revealed tubular cell atrophy, glomerulosclerosis, focal interstitial fibrosis, inflammatory cell reaction, vascular congestion and arteriolar hyalinosis. Also, strong PAS reaction and immune expression of caspase-3 were detected. Administration of RGZ with CsA (GIV) resulted in significant improvement of renal functions and morphology compared to Cs A- treated group. Conclusion: That RGZ has a protective effect in nephrotoxicity induced by CsA administration. It is postulated therefore that PPAR-ү ligands were important for prevention of CsA nephrotoxicity. However, their usefulness in human need to be verified.