Kidney Week

Abstract: FR-PO302

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activates Hedgehog Interacting Protein (Hhip)-Mediated Renal Tubular Cell Senescence in Diabetic Akita Mice

Session Information

• Diabetic Kidney Disease: Basic - 1
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Liao, Min-Chun, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Min-Chun Liao, PhD

• Zhao, Xin-Ping, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Xin-Ping Zhao

• Zhao, Shuiling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shuiling Zhao, PhD

• Su, Ke, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Ke Su, PhD

• Chang, Shiao-Ying, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shiao-Ying Chang, PhD

• Pang, Yuchao, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Yuchao Pang, MS, MSc

• Miyata, Kana, Saint Louis University, St Louis, Missouri, United States

Kana Miyata, MD

• Peng, Junzheng, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Junzheng Peng, MD

• Ingelfinger, Julie R., Harvard Medical School, Boston, Massachusetts, United States

Julie R. Ingelfinger, MD

• Chan, John S.D., Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

John S.D. Chan, PhD

• Zhang, Shao-Ling, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Shao-Ling Zhang, PhD

Background

We recently reported that hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD) (Diabetologia 2023). However, the underlying mechanism(s) are poorly understood. Nuclear factor erythroid 2–related factor 2 (Nrf2) plays a key role in Sglt2 inhibition-reduced tubular cell senescence in DKD (PMID: 34318973); here, we aimed to elucidate the underlying mechanism of Hhip and Nrf2 interaction on tubular senescence in DKD in vivo and in vitro.

Methods

Male Akita, Akita/Nrf2^–/– and Akita/Nrf2^–/– mice with renal proximal tubular cell (RPTC)-specific Nrf2 transgene (Akita/Nrf2^–/–/Nrf2^RPTC-Tg), and their respective control mice (non-Akita or Nrf2^–/–) were studied. Primary RPTCs and human immortalized HK-2 cells were the in vitro model used.

Results

Compared to respective controls at the age of 20 weeks, Akita mice displayed typical DKD characteristics (increased urinary albumin/creatinine ratio and glomerular filtration rate) and renal dysmorphology (renal hypertrophy, glomerulosclerosis and tubulopathy); those changes were attenuated in Akita/Nrf2^–/– mice. As compared with Akita, Akita/Nrf2^–/– mice had less renal tubular Hhip gene expression and decreased tubular senescence as assessed by β-galactosidase activity and p16-, p21-, and p53- immunostaining. However, these protective features were markedly lost in Akita/Nrf2^–/–/Nrf2^RPTC-Tg kidneys. In vitro, Nrf2 activators (oltipraz or CDDO-Me) significantly stimulated Hhip gene expression (promotor activity, Hhip mRNA and protein expression), while also promoted cellular senescence. Those effects were more pronounced under high glucose milieu. In contrast, HK-2 cells with Nrf2 knockout largely prevented the above phenotypes.

Conclusion

Nrf2 activates Hhip gene expression in RPTCs. In diabetes, activation of both Nrf2 and Hhip works in concert to accelerate tubular senescence in DKD.

Funding

• Government Support – Non-U.S.