Podocyte-Specific NRF2 Activity Protects Against Adriamycin-Induced Kidney Injury
- Glomerular Diseases: Podocyte Biology - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
- Hartman, Hannah L., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
- Bondi, Corry D., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
- Wang, Jiaxuan, University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
- Tan, Roderick J., University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania, United States
NRF2 is a key regulator of antioxidant and detoxification pathways in the kidney. KEAP1 is an endogenous inhibitor of NRF2. Various cellular stressors alter KEAP1 binding to NRF2, leading to NRF2 nuclear translocation and upregulation of target antioxidant and detoxification genes. Unexpectedly, NRF2 enhancers increased proteinuria in CKD clinical trials. Our prior work also demonstrated that global NRF2 enhancement exacerbates proteinuria in mouse models of glomerular disease. The kidney cell(s) mediating these effects are not known. Since podocytes are key cells maintaining the glomerular filtration barrier, we hypothesized that podocyte-specific NRF2 activity exacerbates proteinuria and glomerular injury.
We generated podocyte-specific KEAP1 knockout mice (Podo-KEAP1 KO) by crossing Podocin-Cre mice with Keap1 floxed mice. These mice exhibit increased NRF2 activity only in podocytes. We subjected Podo-KEAP1 KO and control littermates to either adriamycin or chronic angiotensin II infusion to induce glomerular injury and proteinuria. Kidney injury was assessed by histologic, biochemical, and molecular indices.
Contrary to our expectations, Podo-KEAP1 KO mice were protected against adriamycin-induced kidney injury, as demonstrated by lower levels of proteinuria, the injury marker NGAL, and fibrosis. Results from glomerular isolates reveal significantly increased antioxidant (Nqo1 and Cat) and a trend to decreased inflammatory responses (IL-1β) that may protect Podo-KEAP1 KO mice from adriamycin injury. However, in the angiotensin II model there was neither improvement nor worsening of disease.
Although prior work demonstrated that global NRF2 enhancement worsens proteinuric CKD, we now show that podocyte-specific NRF2 enhancement protects against adriamycin-induced injury. This may be due to a specific effect of podocyte NRF2 activity to reduce glomerular oxidative stress in this model. Lack of effect in the angiotensin II model suggests a different mechanism of injury. Non-podocyte effects must also mediate CKD exacerbation in both models when NRF2 is globally enhanced. Future studies will determine the cell- and disease-specific effects of NRF2 in CKD and whether podocyte-specific NRF2 can be targeted therapeutically.
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