Targeting of sodium–glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats
| Autor: | Rudolf P. Wüthrich, Daniel Rodriguez, Yang Liu, Olivier Devuyst, Suhua Zhang, Xueqi Wang, Nilufar Mohebbi, Stephan Segerer, Daniela Spichtig, Sarika Kapoor, Changlin Mei, Hermann Koepsell, Andreas L. Serra |
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| Přispěvatelé: | University of Zurich, Mei, Changlin |
| Rok vydání: | 2013 |
| Předmět: |
Male
Time Factors endocrine system diseases 030232 urology & nephrology Kidney 10052 Institute of Physiology chemistry.chemical_compound 0302 clinical medicine Polycystic kidney disease 10035 Clinic for Nephrology Molecular Targeted Therapy Cells Cultured Polycystic Kidney Diseases 0303 health sciences 2727 Nephrology 3. Good health Nephrology Disease Progression Urological Agents Mitogen-Activated Protein Kinases medicine.symptom Glycosuria Heterozygote medicine.medical_specialty MAP Kinase Signaling System Phlorizin Renal function 610 Medicine & health Biology Sodium-Glucose Transport Proteins Excretion 03 medical and health sciences Internal medicine medicine Albuminuria Animals PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology Dose-Response Relationship Drug nutritional and metabolic diseases Kidney metabolism medicine.disease Diuresis Rats Disease Models Animal Ki-67 Antigen Phlorhizin Endocrinology chemistry 570 Life sciences biology Cotransporter |
| Zdroj: | Kidney international |
| ISSN: | 0085-2538 |
| Popis: | Renal tubular epithelial cell proliferation and transepithelial cyst fluid secretion are key features in the progression of polycystic kidney disease (PKD). As the role of the apical renal sodium-glucose cotransporters in these processes is not known, we tested whether phlorizin inhibits cyst growth and delays renal disease progression in a rat model of PKD. Glycosuria was induced by subcutaneous injection of phlorizin in male heterozygous (Cy/+) and wild-type Han:SPRD rats. Phlorizin induced immediate and sustained glycosuria and osmotic diuresis in these rats. Cy/+ rats treated with phlorizin for 5 weeks showed a significant increase in creatinine clearance, a lower 2-kidneys/body weight ratio, a lower renal cyst index, and reduced urinary albumin excretion as compared with vehicle-treated Cy/+ rats. Measurement of Ki67 staining found significantly lower cell proliferation in dilated tubules and cysts of Cy/+ rats treated with phlorizin, as well as a marked inhibition of the activated MAP kinase pathway. In contrast, the mTOR pathway remained unaltered. Phlorizin dose dependently inhibited MAP kinase in cultured tubular epithelial cells from Cy/+ rats. Thus, long-term treatment with phlorizin significantly inhibits cystic disease progression in a rat model of PKD. Hence, induction of glycosuria and osmotic diuresis (glycuresis) by renal sodium-glucose cotransporters inhibition could have a therapeutic effect in polycystic kidney disease. |
| Databáze: | OpenAIRE |
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