Renal tubule-specific Nrf2 deletion ameliorates diabetic kidney disease by attenuating glomerular hypertension and kidney injury in a mouse model of diabetes.
Su Ke, Zhou Jing, Pang Yuchao, Chang Shiao-Ying, Liao Min-Chun, Yang Wen-Xia, Zhao Shuiling, Peng Junzheng, Leal Daniel N, Yamashita Michifumi, Miyata Kana N, Filep Janos G, Ingelfinger Julie R, Zhang Shao-Ling, Chan John S D
Abstract
AIMS/HYPOTHESIS: We previously reported that expression of nuclear factor erythroid 2-related factor 2 (NRF2) is upregulated in the renal tubules of humans with diabetes and in mouse models of diabetes. We hypothesised that Nrf2 deletion would ameliorate renal hyperfiltration and kidney injury in Akita mice (a model of type 1 diabetes). METHODS: Akita Nrf2RT knockout (KO) mice were generated by cross-breeding tubule-specific (Pax8)-Cre mice with Akita Nrf2 floxed mice on a C57BL/6 background. Male non-diabetic control mice (Nrf2fl/fl), Nrf2RT KO mice, Akita Nrf2fl/fl mice and Akita Nrf2RT KO mice were studied up to the age of 20 weeks (n=8 per group). RESULTS: The glomerular filtration rate (GFR), kidney hypertrophy, tubular injury score, glomerular basement membrane thickness, podocyte loss and foot process effacement and urinary albumin-creatinine ratio were significantly increased in Akita Nrf2fl/fl mice and were markedly reduced in Akita Nrf2RT KO mice compared with the corresponding control mice. Attenuation of afferent arteriole vasodilation and efferent arteriole vasoconstriction was observed in Akita Nrf2RT KO mice compared with Akita Nrf2fl/fl mice. Furthermore, downregulation of sodium-glucose co-transporter 2 (SGLT2) and angiotensinogen expression in renal proximal tubules was observed in Akita Nrf2RT KO mice compared with Akita Nrf2fl/fl mice. Treatment of Akita Nrf2RT KO mice with a selective A1 adenosine receptor inhibitor increased GFR and fractional excretion of glucose, suggesting that enhanced adenosine signalling may contribute to the altered renal haemodynamics through tubuloglomerular feedback and reduced glomerular injury associated with RT-specific Nrf2 deletion. CONCLUSIONS/INTERPRETATION: These findings suggest that tubular NRF2 plays an important role in the progression of diabetic kidney disease in Akita mice through modulation of the GFR and expression of SGLT2 and angiotensinogen in renal proximal tubules and tubuloglomerular feedback.
Key Findings
- Renal tubule-specific deletion of Nrf2 in Akita diabetic mice reduced glomerular filtration rate, kidney hypertrophy, tubular injury, and markers of glomerular damage compared to controls.
- Nrf2 deletion attenuated afferent arteriole vasodilation and efferent arteriole vasoconstriction, indicating improved renal hemodynamics.
- Downregulation of sodium-glucose co-transporter 2 (SGLT2) and angiotensinogen expression was observed in renal proximal tubules with Nrf2 deletion, and enhanced adenosine signaling contributed to altered tubuloglomerular feedback.
Clinical Significance
Targeting tubular NRF2 may represent a therapeutic strategy to ameliorate diabetic kidney disease by improving renal function and reducing kidney injury through modulation of oxidative stress and renal hemodynamics.
Citation
Su Ke, Zhou Jing, Pang Yuchaoet al.. Renal tubule-specific Nrf2 deletion ameliorates diabetic kidney disease by attenuating glomerular hypertension and kidney injury in a mouse model of diabetes. Diabetologia. 2026-Oct-17.