Kidney Week

Abstract: SA-PO433

Renal Tubule-Specific NRF2 Deletion Downregulates SGLT2 and Angiotensinogen Expression and Ameliorates GFR and Kidney Injury in Akita Mice

Session Information

• Diabetic Kidney Disease: Basic - II
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

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

Ke Su,

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

Shuiling Zhao,

• Yang, Wenxia, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada

Wenxia Yang,

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

Yuchao Pang,

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

Min-Chun Liao,

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

Junzheng Peng,

• Miyata, Kana N., Saint Louis University, Saint Louis, Missouri, United States

Kana N. Miyata,

• Filep, Janos G., Hopital Maisonneuve-Rosemont, Montreal, Quebec, Canada

Janos G. Filep,

• Ingelfinger, Julie R., Massachusetts General Hospital, Boston, Massachusetts, United States

Julie R. Ingelfinger,

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

Shao-Ling Zhang,

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

John S.D. Chan,

Background

Nuclear factor erthyroid-2 related factor 2 (NRF2) expression is increased in kidneys of mice and patients with diabetes. We have reported that overexpression of NRF2 in renal proximal tubular cells (RPTCs) increases sodium-glucose co-transporter 2 (SGLT2) and angiotensinogen (AGT) expression and exacerbates dysglycemia and progression of nephropathy in type 1 diabetic (T1D) Akita Nrf2^-/-/Nrf2^RPTC transgenic (Tg) mice (Diabetes 2021). However, the pathophysiological role of renal NRF2 in the progression of diabetic kidney disease (DKD) is not well understood. We now report the impact of Nrf2 deletion specifically in renal tubules (RT) of Akita mice on the expression of SGLT2 and AGT in RPTCs in the setting of hyperglycemia and kidney injury.

Methods

Akita RT-specific Nrf2 knock-out (Akita Nrf2^RT KO) mice were generated by crossbreeding Akita with Nrf2^RT KO mice using Pax8-Cre (through crossbreeding male Nrf2 floxed mice with female RT-specific Cre deleter (Pax8-Cre) mice). Immunostaining on kidney sections, Western blot (WB) and real-time qPCR (RT-qPCR) were employed to assess protein and gene expression in isolated RPTs. Physiological and kidney morphological changes were assessed in male Akita Nrf2^RT KO, Akita Nrf2^lox/lox, non-diabetic Nrf2^lox/lox and Nrf2^RT KO mice at the age of 10 to 20 weeks.

Results

SGLT2 and AGT expression in RPT were significantly lower in Akita Nrf2^RT KO mice cf. to Akita mice. Glomerular filtration rate (GFR) was increased in Akita mice but was normalized (reversed glomerular hyperfiltration) in Akita Nrf2^RT KO mice. Fasting blood glucose, glomerular tuft volume, RPTC volume, tubular luminal dilatation, tubular injury score, kidney weight and urinary albumin-creatinine ratio (ACR) were significantly increased in Akita mice vs nondiabetic Nrf2^lox/lox and Nrf2^RT KO mice. These abnormalities were greatly reduced in Akita Nrf2^RT KO mice, except for fasting blood glucose. Fractional excretion of glucose was increased in Akita mice and increased further in Akita Nrf2^RT KO mice.

Conclusion

Our results show that RT-Nrf2 deletion ameliorates GFR and kidney injury in Akita mice, indicating renal NRF2 is important in tubuloglomerular feedback via down-regulation of intrarenal SGLT2 and AGT expression.

Funding

• Government Support – Non-U.S.