Kidney Week

Abstract: SA-PO282

TW-37, a Senolytic Agent and Inhibitor of KIM-1-Mediated Endocytosis, Reduces KIM-1 Expression, NF-κB-IL-1β Axis, and p16-Mediated Cellular Senescence

Session Information

• Diabetic Kidney Disease: Basic - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Mori, Yutaro, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Yutaro Mori, MD, PhD, FASN

• Mori, Makiko, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Makiko Mori

• Nakao, Yuki, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Yuki Nakao, MS, MSc

• Sekiguchi, Yuta, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Yuta Sekiguchi, MD

• Mandai, Shintaro, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Shintaro Mandai, MD, PhD, FASN

• Ando, Fumiaki, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Fumiaki Ando, MD, PhD

• Susa, Koichiro, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Koichiro Susa, MD, PhD

• Mori, Takayasu, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Takayasu Mori, MD, PhD

• Sohara, Eisei, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Eisei Sohara, MD, PhD

• Uchida, Shinichi, Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Shinichi Uchida, MD, PhD

Background

Chronic KIM-1 expression is known to be detrimental. Previously, we identified TW-37 as an inhibitor for KIM-1 mediated endocytosis. We discovered KIM-1-mediated endocytosis of palmitic acid-bound albumin leads NLRP3 inflammasome activation, DNA damage response, cell cycle arrest, cellular senescence and inflammatory fibrotic cytokine production. TW-37 is also known as a senolytic which induce cell death on senescent cells. In this study, we tested relatively long-term effects of TW-37 on primary human renal proximal tubular epithelial cells (hRPTECs).

Methods

We established primary hRPTECs from a patient’s resected kidney due to a malignancy with a written informed consent. Uninvolved parts of kidneys were cultured on serum-free media containing epidermal growth factor. We seeded 6 x 10⁵cells on day 0 and changed the medium to 10% fetal bovine serum-DMEM (high glucose) containing TW-37 or control DMSO on day 2. We cultured the cells for 8 days (day 2-10) with changing media containing TW-37 or DMSO. KIM-1, NF-κB, IL-1β, p16, caspase-3 and PD-L1 were evaluated by western blotting.

Results

Treatment of TW-37 reduced KIM-1 expression. It also reduced NF-κB and IL-1β, probably indicating NF-κB-NLRP3 inflammasome-IL-1β axis was upregulated. In the control p16 was expressed. Treatment of TW-37 reduced expression of p16 but did not increase expression of caspase-3, suggesting that TW-37 may have non-apoptotic anti-senescence effects. Finally, TW-37 reduced PD-L1 expression.

Conclusion

TW-37 as known for a senolytic and an endocytosis inhibitor for KIM-1 mediated endocytosis may induce intracellular anti-inflammatory and anti-senescence process by downregulating KIM-1, which can be renoprotective effects.

Funding

• Private Foundation Support