Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats

• Published in: PloS one Vol. 10; no. 4; p. e0125603
• Main Authors: Kapoor, Sarika, Rodriguez, Daniel, Riwanto, Meliana, Edenhofer, Ilka, Segerer, Stephan, Mitchell, Katharyn, Wüthrich, Rudolf P
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.04.2015; Public Library of Science (PLoS)
• Subjects: Albuminuria - drug therapy; Animals; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - pharmacology; Biopsy; Body Weight - drug effects; Cell proliferation; Cell Proliferation - drug effects; Creatinine; Cyclic AMP - metabolism; Cysts; Diabetes; Disease Models, Animal; Disease Progression; Diuresis; Diuresis - drug effects; Electrolytes - blood; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Excretion; Fuel consumption; Glucose; Glucosides - administration & dosage; Glucosides - pharmacology; Hospitals; Hyperfiltration; Hyperglycemia; Inhibition; Inhibitors; Kidney - diagnostic imaging; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Function Tests; Kidneys; Male; Nephrology; Physiology; Plasma; Polycystic kidney; Polycystic kidney disease; Polycystic Kidney Diseases - diagnosis; Polycystic Kidney Diseases - drug therapy; Polycystic Kidney Diseases - metabolism; Rats; Reabsorption; Renal function; Rodents; Sodium; Sodium-glucose cotransporter; Sodium-Glucose Transport Proteins - antagonists & inhibitors; Ultrasonic imaging; Ultrasonography; Ultrasound; Ultrasound imaging; Urine; Weight; United States > US; Switzerland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125603

The sodium-glucose-cotransporter-2 (SGLT2) inhibitor dapagliflozin (DAPA) induces glucosuria and osmotic diuresis via inhibition of renal glucose reabsorption. Since increased diuresis retards the progression of polycystic kidney disease (PKD), we investigated the effect of DAPA in the PCK rat model of PKD. DAPA (10 mg/kg/d) or vehicle was administered by gavage to 6 week old male PCK rats (n=9 per group). Renal function, albuminuria, kidney weight and cyst volume were assessed after 6 weeks of treatment. Treatment with DAPA markedly increased glucose excretion (23.6 ± 4.3 vs 0.3 ± 0.1 mmol/d) and urine output (57.3 ± 6.8 vs 19.3 ± 0.8 ml/d). DAPA-treated PCK rats had higher clearances for creatinine (3.1 ± 0.1 vs 2.6 ± 0.2 ml/min) and BUN (1.7 ± 0.1 vs 1.2 ± 0.1 ml/min) after 3 weeks, and developed a 4-fold increase in albuminuria. Ultrasound imaging and histological analysis revealed a higher cyst volume and a 23% higher total kidney weight after 6 weeks of DAPA treatment. At week 6 the renal cAMP content was similar between DAPA and vehicle, and staining for Ki67 did not reveal an increase in cell proliferation. In conclusion, the inhibition of glucose reabsorption with the SGLT2-specific inhibitor DAPA caused osmotic diuresis, hyperfiltration, albuminuria and an increase in cyst volume in PCK rats. The mechanisms which link glucosuria to hyperfiltration, albuminuria and enhanced cyst volume in PCK rats remain to be elucidated.