Kidney Week

Abstract: SA-PO703

Canagliflozin Reduces Podocyte Hypertrophic Stress and Progression of Nephropathy by Suppressing the mTOR/p70S6K/cyclin D1 Signaling Pathway in a Model of Obesity-Related Nephropathy

Session Information

• Glomerular Diseases: Therapeutic Strategies
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Suzuki, Miho, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Miho Suzuki, MD

• Fukuda, Akihiro, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Akihiro Fukuda, MD, PhD

• Kurimoto, Ryo, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Ryo Kurimoto, MBBS

• Kudo, Akiko, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Akiko Kudo, MD

• Nakata, Takeshi, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Takeshi Nakata, MD

• Shibata, Hirotaka, Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Faculty of Medicine, Oita University, Yufu, Oita, Japan

Hirotaka Shibata, MD, PhD

Background

We recently suggested that SGLT2 inhibitors (SGLT2i) suppressed podocyte hypertrophy in models of obesity-related nephropathy (ASN2023). In this study, we examined the underlying mechanisms of the podocyte-protective effects of SGLT2i.

Methods

Zucker fatty rats with non-diabetic obesity were divided into three groups (non-treated: n=6, SGLT2i: n=6, calorie restriction (CR): n=6). Starting at 12 weeks, both the non-treated and SGLT2i groups were fed same quantities of diet. From 24 weeks, the SGLT2i group received canagliflozin (10 mg/kg/day) for 8 weeks, while the CR group was on a diet restricted to match the urinary glucose excretion of the SGLT2i group. Kidney tissue and urine samples were collected at 32 weeks to assess podocyte injury through measurements of urinary protein, urinary sediment podocin (U-sed pod) mRNA using qRT-PCR, glomerular volume (GV), podocyte volume (PV), and podocyte density (PD). To investigate the underlying mechanism, RNA sequencing of the renal cortex was performed for a Zucker Lean (ZL) group as a control, and for the non-treated and SGLT2i groups. Additionally, the IGF-1/mTOR pathway was examined through phosphorylated S6 (pS6) immunostaining and IGF-1 expression using ELISA in the kidney cortex of all four groups.

Results

In the SGLT2i group, body weight, urinary protein, GV, PV, and U-sed pod mRNA significantly decreased, while PD increased, compared to the non-treated group. These effects were more pronounced than those observed in the CR group. RNA sequencing revealed a significant increase in cyclin D1 expression in the non-treated group, which plays an important role in cell cycle and hypertrophy, but a decrease in the SGLT2i group. Western blot analysis confirmed these trends in cyclin D1 expression. Additionally, the expression of the IGF-1/mTOR pathway components (IGF-1 and phosphorylated S6), which are upstream of cyclin D1, was upregulated in the non-treated group but downregulated in the SGLT2i group. The CR group had intermediate levels between the non-treated and SGLT2i groups.

Conclusion

In obesity-related nephropathy, SGLT2i may protect podocytes and reduce hypertrophic stress by suppressing the mTOR/p70S6K/cyclin D1 signaling pathway, independently of reductions to body weight.

Funding

• Government Support – Non-U.S.