Electrolyte Blood Press.  2020 Jun;18(1):1-9. 10.5049/EBP.2020.18.1.1.

Urinary Concentration Defect and Renal Glycosuria in Cyclosporine-treated Rats

• Lee JH
• Kim SA
• Jo CH
• Lee CH
• Kim GH

• KMID: 2503008
• DOI: http://doi.org/10.5049/EBP.2020.18.1.1

Abstract

Background
Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity.
Methods
We explored two possible mechanisms that may underlie cyclosporineinduced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II).
Results
In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88 ±3%, p<0.05).
Conclusion
Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Keyword

Aquaporin-2; Cyclosporine; GLUT2; Osmotic diuresis; Water diuresis