Effect of Sodium-Glucose Cotransport Inhibition on Polycystic Kidney Disease Progression in PCK Rats.
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.
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Sarika
S
Kapoor
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Daniel
D
Rodriguez
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Meliana
M
Riwanto
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Ilka
I
Edenhofer
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Stephan
S
Segerer
Clinic for Equine Internal Medicine, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland.
Katharyn
K
Mitchell
Division of Nephrology, University Hospital, Zürich, Switzerland; Institute of Physiology, University of Zürich, Zürich, Switzerland.
Rudolf P
RP
Wüthrich
D000419:Albuminuria / Q000188:drug therapy; D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001706:Biopsy; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004231:Diuresis / Q000187:drug effects; D004573:Electrolytes / Q000097:blood; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005960:Glucosides / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D007690:Polycystic Kidney Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D051381:Rats; D051247:Sodium-Glucose Transport Proteins / Q000037:antagonists & inhibitors*; D014463:Ultrasonography
D001559:Benzhydryl Compounds; D004573:Electrolytes; D005960:Glucosides; D051247:Sodium-Glucose Transport Proteins; C529054:dapagliflozin; D000242:Cyclic AMP