Renal tubule-specific Nrf2 deletion ameliorates diabetic kidney disease by attenuating glomerular hypertension and kidney injury in a mouse model of diabetes.

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). 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). 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. 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.