Volume 84, Issue 5, Pages (November 2013)

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Volume 84, Issue 5, Pages 962-968 (November 2013) Targeting of sodium–glucose cotransporters with phlorizin inhibits polycystic kidney disease progression in Han:SPRD rats Xueqi Wang, Suhua Zhang, Yang Liu, Daniela Spichtig, Sarika Kapoor, Hermann Koepsell, Nilufar Mohebbi, Stephan Segerer, Andreas L. Serra, Daniel Rodriguez, Olivier Devuyst, Changlin Mei, Rudolf P. Wüthrich Kidney International Volume 84, Issue 5, Pages 962-968 (November 2013) DOI: 10.1038/ki.2013.199 Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 1 Diuresis, osmolar excretion, and renal function in control (+/+) and cystic (Cy/+) male Han:SPRD rats treated with vehicle (propylene glycol; CON) or phlorizin (PHLO). (a) Course of diuresis, (b) 24-h osmolar excretion, (c) plasma creatinine, and (d) creatinine clearance from baseline to days 17 and 35 of treatment. **P<0.01, ***P<0.001 when comparing Cy/+ CON and Cy/+ PHLO at each time point. #P<0.05 when comparing Cy/+ and +/+ group. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 2 Albumin excretion in Cy/+ and +/+ rats after 5 weeks of treatment with vehicle (propylene glycol; CON) or phlorizin (PHLO). (a) Urine albumin concentration (Cy/+ CON: n=7; Cy/+ PHLO: n=10; +/+ CON: n=5; +/+ PHLO: n=3). **P<0.01; (b) Urine sample SDS–polyacrylamide gel electrophoresis. Each lane shows a urine sample of a single rat, each group shows representative samples from three rats. Loading volumes were corrected for diuresis and amounted to 15μl for vehicle-treated rats, and 45μl for phlorizin-treated rats. Arrow shows the band for albumin. M, marker. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 3 Effect of phlorizin on kidney weight and cyst index. Ratio of (a) 2-kidneys/body weight (2K/BW) and (b) cyst index in male Cy/+ rats treated daily for 5 weeks with vehicle (propylene glycol; CON; n=7) or phlorizin (PHLO, n=10). *P<0.05, ***P<0.001. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 4 Effect of phlorizin on renal histology. Renal histology (periodic acid–Schiff) in (a, c) vehicle-treated (propylene glycol; CON) and (b, d) phlorizin-treated (PHLO) male Cy/+ rats. Scale bar is 2000μm in a and b, and 200μm in c and d. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 5 Representative areas of Ki67 immunohistochemical staining in Cy/+ rat kidneys. (a) Cy/+ CON (cyst), (b) Cy/+phlorizin (PHLO; cyst), (c) Cy/+ CON (dilated tubule), (d) Cy/+ PHLO (dilated tubule), (e) +/+ CON, and (f) +/+ PHLO. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 6 Effect of phlorizin on ERK and S6K phosphorylation. (a) Western blot analysis and (b) densitometry for mammalian target of rapamycin and mitogen-activated protein kinase pathway in +/+ and Cy/+ kidney. Cy/+ rats show enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and S6K compared with wild-type +/+ animals. In phlorizin-treated Cy/+ rats, the phosphorylation of ERK and the pERK/total ERK ratio is significantly reduced, whereas the phosphorylation of S6K and the pS6K/total S6K ratio is unchanged. CON, propylene glycol treated; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PHLO, phlorizin. *P<0.05, ***P<0.001. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions

Figure 7 Western blot analysis for phosphorylated extracellular signal-regulated kinase 1/2 (pERK; top) and total ERK (bottom) in response to phlorizin treatment (0–1000μmol/l) in cultured Cy/+ tubular epithelial cell (TEC). TEC cultured from +/+ kidneys served as control. Bottom bar graph shows the densitometric pERK/total ERK ratios. Kidney International 2013 84, 962-968DOI: (10.1038/ki.2013.199) Copyright © 2013 International Society of Nephrology Terms and Conditions