Correlation between cyclosporine-induced nephrotoxicity in reduced nephron mass and expression of kidney injury molecule-1 and aquaporin-2 gene.
Sirolimus (SRL) has been shown to exacerbate cyclosporine (CsA)-induced nephrotoxicity. The expression of the kidney injury molecule-1 (KIM-1) is markedly upregulated in the postischemic rat kidney. We sought to correlate drug-induced nephrotoxicity and the expression of KIM-1 and aquaporin-2 (AQP-2) in male PVG rats with 2 kidneys (2K), 1 kidney (1K), and half a kidney (1/2K) treated with SRL alone, CsA alone, or a combination of both (SRL-CsA). After 7 days of treatment, the 2K group treated with SRL-CsA showed a significant decrease in creatinine clearance compared with the 2K SRL alone and 2K CsA alone groups (1.2 vs 2.47 vs 2.46 mL/min; P < .001). There was a trend toward deterioration of creatinine clearance in the 1K and 1/2K groups treated with SRL-CsA. The KIM-1 expression in the 2K SRL-CsA group was significantly upregulated compared with that in the 2K SRL alone and 2K CsA alone groups (P = .02). The AQP-2 expression was comparable in the 3 groups. After 1 week of treatment washout, the 2K, 1K, and 1/2K groups treated with SRL alone demonstrated a significantly higher creatinine clearance rate than did the groups treated with SRL-CsA (P = .04, P = .02, and P = .004). The expression of KIM-1 and AQP-2 was similar among the treatment groups. SRL-CsA-induced nephrotoxicity resulted in overexpression of KIM-1, suggesting injury to the proximal tubule. Treatment with SRL alone may enable earlier reversal of tubular injury.
Hong
M E
ME
Division of Pediatric Renal Diseases and Hypertension, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Hong
J C
JC
Stepkowski
S
S
Kahan
B D
BD
D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D016572:Cyclosporine / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D023421:Models, Animal; D009399:Nephrons / Q000033:anatomy & histology* / Q000187:drug effects / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051399:Aquaporin 2; D015815:Cell Adhesion Molecules; D016572:Cyclosporine; D008565:Membrane Proteins; D012313:RNA; C496025:Aqp2 protein, rat; C110936:Havcr1 protein, rat