EXPRESSION OF KIDNEY INJURY AND FUNCTIONAL GENES CORRELATE WITH REDUCED NEPHRON MASS IN CYCLOSPORINE-INDUCED NEPHROTOXICITY:

O115* Aims: Cyclosporine (CsA)-induced nephrotoxicity is exacerbated by sirolimus (SRL) especially in patients with reduced nephron mass. We examined the mechanism of nephrotoxicity by measuring expression of kidney functional genes: kidney injury molecule-1 (KIM-1); aquaporin-2 (AQP-2); paracellin-1 (PCLN-1), sodium hydrogen exchanger-3 (NHE-3), and sodium/phosphate cotransporter-2 (NaPi-2). Methods: Renal function was tested in salt-depleted rats bearing two kidneys (2K) or only one-half kidney (½K). These rats (5/group) were untreated or treated (p.o.) for 7 or 28 days with CsA (5 mg/kg) and/or SRL (0.8 mg/kg). Serum creatinine clearance (CrCl) and other biochemistries were compared using ANOVA test. PCR-based method was used to measure KIM-1, AQP-2, PCLN-1, NHE-3, and NaPi-2 mRNA expression. Results: At 7 days in 2K, CrCl was similar in untreated (2.7±0.7 ml/min), as well as in CsA- (2.3±0.9 ml/min; NS) and SRL- (2.5±0.3 ml/min; NS) treated groups, but decreased in CsA/SRL-treated group (1.2±0.1 ml/min; p<0.05). Although reduced nephron mass to ½K significantly decreased CrCl values in all groups [control, 0.9±0.3 ml/min; CsA, 0.6±0.3 ml/min; and SRL, 0.8±0.4 ml/min], it most dramatically affected CsA/SRL group (0.4±0.1 ml/min; p<0.05). The extended treatment to 28 days was again significantly worse for ½K compared to 2K. These results were reflected by PCR results: KIM-1 mRNA expression was low in normal 2K as well as 2K treated with CsA and SRL alone, but increased in two-drug combination (p=0.01; n=3). In contrast, KIM-1 mRNA level was elevated in ½K in all groups (p<0.05; n=3). Furthermore, in comparison to 2K, AQP-2, PCLN-1, NHE-3 and NaPi-2 mRNA levels were decreased in ½K (p<0.05; n=3), especially in CsA/SRL group (p<0.01; n=3). Conclusions: Impaired kidney function is accentuated by reduced nephron mass in CsA- and CsA/SRL-induced nephrotoxicity. These changes correlate with elevated expression of kidney injury gene (KIM-1) as possible activation of kidney protective mechanism and decreased expression of kidney functional genes (AQP-2, PCLN-1, NHE-3 and NaPi-2).