Kidney Week

Abstract: SA-PO815

Genetic Nrf2 Enhancement Increases Proteinuric Renal Injury

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Rush, Brittney M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Brittney M. Rush,

• Bondi, Corry D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Corry D. Bondi,

• Barry, Kacie, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Kacie Barry,

• Stocker, Sean D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Sean D. Stocker,

• Jobbagy, Soma, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Soma Jobbagy,

• Stolz, Donna Beer, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Donna Beer Stolz,

• Chartoumpekis, Dionysios, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Dionysios Chartoumpekis,

• Kensler, Thomas W., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Thomas W. Kensler,

• Tan, Roderick J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Roderick J. Tan,

Background

Proteinuric chronic kidney disease (CKD) is a major cause of progressive renal failure and has limited therapies. Nrf2 (nuclear factor erythroid 2 like 2) is a transcription factor that upregulates cytoprotective mechanisms including antioxidants and detoxifying genes. Keap1 (kelch-like ECH-associated protein 1) binds and inhibits Nrf2 under normal conditions to prevent activity. Under conditions of oxidative stress or chemical exposure, the Keap1 repressor releases Nrf2 which then initiates target gene transcription. While this might be expected to prevent disease, both preclinical and clinical data have suggested that Nrf2 could paradoxically aggravate proteinuria. We therefore hypothesized that Nrf2 activity accelerates progression of proteinuric CKD.

Methods

Keap1 hypomorphic mutant mice have reduced Keap1 expression and enhanced Nrf2 activity. Wild-type mice and Keap1 hypomorphs were subjected to a variety of proteinuric injuries including continuous angiotensin II infusion, adriamycin, and albumin overload models. Urinary albumin excretion was measured with ELISA, and glomerular damage assessed via assessment of foot process effacement, nephrin, and Wilms Tumor 1 (WT1). Systemic blood pressure was measured with radiotelemetry, and glomerular filtration rate (GFR) was determined with FITC-sinistrin. The synthetic triterpenoid, CDDO-Im, was used in the adriamycin model to upregulate Nrf2 activity.

Results

Compared to wild-type mice, Keap1 hypomorphs had significantly increased proteinuria in all disease models. This was associated with worsened podocyte foot process effacement and decreased nephrin and WT1, indicating increased glomerular injury. We did not detect any increase in GFR in the mutants to explain this difference. While there were mild elevations in the systolic, diastolic, and mean blood pressures in the Keap1 hypomorphs before and after angiotensin II infusion, the proteinuria was out of proportion to these differences. Treatment of wild-type mice with CDDO-Im enhanced Nrf2 activity but also increased mortality after adriamcyin exposure.

Conclusion

Genetic Nrf2 upregulation significantly promotes glomerular injury and lethality in proteinuric kidney injury models. This phenomenon is partly explained by higher blood pressure in hypomorphic mice but other mechanisms likely play a role.

Funding

• NIDDK Support