Long-term treatment with cyclosporine decreases aquaporins and urea transporters in the rat kidney

• Published in: American journal of physiology. Renal physiology 2004-07, Vol.56 (1), p.F139-F151
• Main Authors: LIM, Sun-Woo, CAN LI, JIN KIM, YANG, Chul-Woo, SUN, Bo-Kyung, HAN, Ki-Hwan, KIM, Wan-Young, OH, Yoon-Wha, LEE, Jong-Un, KADOR, Peter F, KNEPPER, Mark A, SANDS, Jeff M
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cells; Fundamental and applied biological sciences. Psychology; Kidneys; Pharmaceuticals; Rodents; Urine; Vertebrates: urinary system
• ISSN: 1931-857X; 1522-1466

The aim of this study was to evaluate the long-term effects of cyclosporine (CsA) treatment on urinary concentration ability. Rats were treated daily for 4 wk with vehicle (VH; olive oil, 1 ml/kg sc) or CsA (15 mg/kg sc). The influence of CsA on the kidney's ability to concentrate urine was evaluated using functional parameters and expression of aquaporins (AQP1-4) and of urea transporters (UT-A-1-3, and UT-B). Plasma vasopressin levels and the associated signal pathway were evaluated, and the effect of vasopressin infusion on urine concentration was observed in VH- and CsA-treated rats. Toxic effects of CsA on tubular cells in the medulla as well as the cortex were evaluated with aldose reductase (AR), Na-K-ATPase-alpha1 expression, and by determining the number of terminal transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells. Long-term CsA treatment increased urine volume and fractional excretion of sodium and decreased urine osmolality and free-water reabsorption compared with VH-treated rats. These functional changes were accompanied by decreases in the expression of AQP (1-4) and UT (UT-A2, -A3, and UT-B), although there was no change in AQP2 in the cortex and outer medulla and UT-A1 in the inner medulla (IM). Plasma vasopressin levels were not significantly different between two groups, but infusion of vasopressin restored CsA-induced impairment of urine concentration. cAMP levels and Gsalpha protein expression were significantly reduced in CsA-treated rat kidneys compared with VH-treated rat kidneys. CsA treatment decreased the expression of AR and Na-K-ATPase-alpha1 and increased the number of TUNEL-positive renal tubular cells in both the cortex and medulla. Moreover, the number of TUNEL-positive cells correlated with AQP2 or UT-A3) expression within the IM. In conclusion, CsA treatment impairs urine-concentrating ability by decreasing AQP and UT expression. Apoptotic cell death within the IM at least partially accounts for the CsA-induced urinary concentration defect. [PUBLICATION ABSTRACT]