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Abstract: TH-PO779

SGLT2 Inhibitor Suppresses Progression of Obesity-Related Nephropathy Induced by Podocyte Hypertrophic Stress

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Suzuki, Miho, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Fukuda, Akihiro, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Kurimoto, Ryo, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Uchida, Hiroki, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Kudo, Akiko, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Nakata, Takeshi, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
  • Shibata, Hirotaka, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan
Background

We recently reported that podocyte hypertrophic stress occurred relatively early during the onset of nephropathic progression in a rat model of type 2 diabetes-related nephropathy. In this study, we evaluated the progression of obesity-related nephropathy (ORN) caused by podocyte hypertrophic stress and the efficacy of an SGLT2 inhibitor (SGLT2i) in obese rat models.

Methods

To investigate the ORN progression, we used 8-week-old Zucker fatty (ZF) rats exhibited non-diabetic obesity model (n = 6), and Zucker lean (ZL) rats as a control model (n = 6). Kidney biopsies and urine samples were collected at 16, 24, and 32 weeks of age. Next, to investigate the effect of an SGLT2i, ZF rats were divided into two groups (SGLT2i: n = 6, non-treated: n = 6); beginning at 12 weeks of age, both groups were fed the same amount of diet. From 24 weeks of age, the SGLT2i group received canagliflozin 10 mg/kg/day for 8 weeks. Kidney tissues and urine samples were collected at 32 weeks of age. We measured urinary sediment podocin (U-sed pod) mRNA using qRT-PCR, glomerular volume (GV), podocyte volume (PV), and podocyte density (PD) to evaluate the podocyte injury.

Results

ZF rats were significantly heavier than ZL rats during the entire observation period. The urinary protein (UP) excretion level in ZF rats began to significantly increase at 16 weeks of age and became 20-fold greater than the level in ZL rats at 32 weeks of age. Significant increases in the GV, PV, and U-sed pod mRNA level, along with a decrease in PD, were observed in ZF rats from 16 to 32 weeks of age. Neither non-treated nor SGLT2i groups were hyperglycemic, and no changes in blood pressure occurred during the observation period. Compared with non-treated group, SGLT2i group exhibited significant weight loss, approximately 50% decrease in UP, significant reductions in the GV and PV, an increased PD (p < 0.01), and decreased U-sed pod mRNA (p < 0.01). SGLT2i group exhibited a significant increase in urinary sodium excretion (p < 0.01) and restored creatinine clearance to the level in control group.

Conclusion

Quantitative and morphological assessment of podocytes suggest that podocyte hypertrophic stress causes ORN progression. An SGLT2i may suppress podocyte hypertrophic stress by inhibiting glomerular hyperfiltration, and progression of ORN.

Funding

  • Government Support – Non-U.S.