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Abstract: PO0916

Loss of Nrf2 Exacerbates Diabetic Kidney Disease in Akita Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Liu, Yexin, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  • Uruno, Akira, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  • Yamamoto, Masayuki, Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
Background

Diabetic kidney disease (DKD) is a devastating microvascular complication with considerable mortality in patients with diabetes mellitus. Excessive reactive oxygen species and inflammation have been identified as major components in the progression of this microvascular complication. Transcription factor Nrf2 (NF-E2-related factor-2), which plays essential roles in protection against oxidative/xenobiotic stresses, is known to alleviate inflammation and oxidative tissue damage. We hypothesized that keeping Nrf2 activated is beneficial for the treatment of DKD.

Methods

To clarify roles Nrf2 plays in the pathogenesis of DKD, we generated Nrf2-knockout Akita mice (Akita::Nrf2–/–) by crossing Ins2Akita/+ (Akita) mice (C57BL/6J) with Nrf2 knockout (Nrf2–/–) mice (C57BL/6J). Phenotypic parameters of male mice were measured, and samples were harvested from the mice at 4 months.

Results

We found that Akita::Nrf2–/– mice displayed more pronounced hyperglycemia and diabetes symptoms than Akita mice did. While expression of Nrf2-tageted genes Nqo1 and Hmox1 was induced in Akita mouse kidneys; the expression was significantly reduced in kidneys of Akita::Nrf2–/– mice. Histologically, Akita mice showed modest mesangial expansion, but Akita::Nrf2–/– mouse glomeruli showed marked distended capillary loops suggesting enhanced mesangiolysis. Akita::Nrf2–/– mice exhibited dilated distal tubules mainly within cortex, which might be associated with osmotic polyuria and oxidative stress-mediated injury; this notion was supported by increased tubular staining of oxidative stress marker 8-OHdG. Nrf2-deficiency in Akita mice contributed to the decrease of glutathione (GSH), which was assessed by in situ matrix-assisted laser-desorption/ionization mass-spectrometry imaging (MALDI-MSI) and lowered expression of GSH-synthesis related genes. Kidneys of Akita::Nrf2–/– mice suffered from severe inflammation, which was evidenced by increased infiltrated monocytes/macrophages and elevated pro-inflammatory cytokine expression. Interstitial fibrosis was developed in the Akita::Nrf2–/– mouse kidneys along with increased expression of fibrogenic genes.

Conclusion

These results demonstrate that Nrf2-deficiency exacerbated inflammatory response, oxidative stress and interstitial fibrosis in the Akita mouse kidneys, indicating that Nrf2 plays important roles in the protection of DKD kidneys.

Funding

  • Government Support - Non-U.S.