Abstract: TH-PO1082
Genetic or Pharmacologic Activation of Nrf2 Worsens Glomerular Injury and Proteinuria
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Rush, Brittney M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Bondi, Corry D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Stocker, Sean D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Tan, Roderick J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Proteinuric chronic kidney disease (CKD) is a major cause of progressive renal failure. Nrf2 (nuclear factor 2 erythroid 2) is a transcription factor and master regulator of a multitude of target genes with roles in antioxidant protection, electrophile detoxification, and overall cytoprotection. Nrf2-activating compounds such as CDDO-Me (bardoxolone methyl) and CDDO-Im have been and continue to be explored as treatments for proteinuric CKD in both clinical trials and experimental animal models. The results of some of these studies have suggested that Nrf2 may paradoxically increase proteinuria. To examine this, we tested the effects of genetic or pharmacologic Nrf2 activation on proteinuria in mice.
Methods
Wild type mice and mice with genetic Nrf2 activation (via reduction in the Nrf2 inhibitor Keap1) were compared. Proteinuria was induced experimentally via exposure to 1) adriamycin, 2) angiotensin II, or 3) albumin overload. Injury was assessed with urine albumin excretion, immunohistochemistry, podocyte foot process effacement, and expression of injury genes. Systemic blood pressures were measured with radiotelemetry. We also examined the effect of pharmacologic Nrf2 activation by CDDO-Im in wild type mice during proteinuric injury.
Results
There were no differences in proteinuria at baseline in the wild type and mutant mice. However, genetic Nrf2 activation led to increases in proteinuria in all three proteinuria models, and this was associated with worsened glomerular injury, podocyte foot process effacement, and renal fibrosis. Blood pressures were slightly higher in the mutant mice, due to a lack of dipping during the sleep cycle. In wild type mice, the addition of CDDO-Im to angiotensin-induced injury led to a dramatic increase in proteinuria which could be reversed upon CDDO-Im withdrawal.
Conclusion
Both genetic and pharmacologic Nrf2 activation led to increased proteinuria after injury. This appears to have deleterious effects on the kidney chronically. Increased blood pressures may contribute to this effect. Our results suggest that Nrf2 activation should be used cautiously in proteinuric CKD.
Funding
- NIDDK Support