Kidney Week

Abstract: SA-PO1181

Autophagy Attenuation-Induced LSD1 Enrichment Promotes Renal Tubular Cell Senescence and Kidney Aging

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Zhang, Yingying, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Yingying Zhang, MD, PhD

• Li, Xiaoyan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaoyan Li, MD, PhD

• Yu, Chen, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Chen Yu, MD, PhD

• Li, Xiaogang, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Xiaogang Li, PhD

Background

The process of population aging will inevitably lead to an increase in age-related comorbidities, including CKD. Alterations of epigenetic modifications are associated with aging at various levels, making them promising targets for interventions against age-related CKD. Lysine-specific demethylase 1 (LSD1) as the first identified histone demethylase plays a critical role in a variety of diseases. However, the role of LSD1 in senescence and kidney aging remains unknown.

Methods

To explore the role and mechanisms of LSD1 in renal tubular senescence and kidney aging, we treated renal tubular epithelial cells with oxidative stress injury agent D-Gal and DNA damaging agent etoposide (ETO) and wild type mice with ionizing radiation (IR) plus an LSD1 specific inhibitor, ORY1001.

Results

The protein level of LSD1, but not its mRNA, was increased in 22-month-old mouse kidneys compared to that in 2-month-old mouse kidneys. The expression of LSD1 protein was also increased in mouse IMCD cells treated with D-gal or ETO. Inhibition of autophagy with its inhibitor Lys05 resulted in a dose-depedent increase of LSD1 protein. We found that LSD1 interacted with autophagy proteins, LC3 and Beclin1, and these interactions subjected to autophagy mediated LSD1 degradation, suggesting a mechanism of that the downregulation of autophagy contributes to the upregulation of LSD1 in senescent cells and aged kidneys. We further found that LSD1 bound to the promoters of p16^ink4a and p21^cip-2, two senescence markers, in renal tubular epithelial cells and targeting LSD1 with its specific inhibitor, ORY100, or siRNA decreased their expression in those cells induced by ETO, supporting a promoting role of LSD1 in senescence. Irradiation（IR） induces high levels of DNA damage which often leads to cellular senescence in vivo. We found that treatment with IR increased LSD1 protein in IR treated kidneys, and administration of ORY-100 demonstrated a protection from IR-induced gray hairs seen in vehicle treated wild type mice and decreased IR-induced accumulation of senescent cells in kidneys.

Conclusion

This study indicates a role of LSD1 in promoting senescence and kidney aging, and a mechanism of that the upregulation of LSD1 is subjected to impaired autophagy in these processes. Our study places an emphasis that LSD1 has potential as a therapeutic target for the delay of kidney aging.

Funding

• NIDDK Support