Kidney Week

Abstract: FR-PO087

Nrf2 Interactions with the HIF System May Determine Long Term Outcomes After AKI

Session Information

• AKI: Tubules, Metabolism, New Models
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

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

Corry D. Bondi,

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

Brittney M. Rush,

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

Roderick J. Tan,

Background

Acute kidney injury (AKI) affects up to 1 in 5 hospitalized patients and is associated with an increased risk of developing chronic kidney disease. AKI is commonly caused by ischemia and proximal tubular epithelia are particularly vulnerable to injury. HIF-1α (Hypoxia-inducible factor-1α) and Nrf2 (Nuclear factor erythroid 2-related factor 2) are transcription factors with protective effects against AKI. Studies suggest an association between HIF system activation and Nrf2 activity but this has not been extensively studied in the kidney.

Methods

C57BL/6 mice were subjected to kidney ischemia-reperfusion to induce AKI. Ischemia times were titrated to induce mild to severe injury and kidneys were harvested at various acute and chronic timepoints post-reperfusion. To simulate mild and severe injury conditions in vitro, proximal tubular HK-2 cells were exposed to either nutrient replete or nutrient deficient conditions, respectively, in the presence of HIF activation with cobalt chloride (CoCl₂). Immunoblotting, qPCR, RNA interference, serum creatinine, and histologic methods were used.

Results

Kidneys obtained 24 h after mild injury had elevated protective Nrf2 activity, as evidenced by expression of the Nrf2 target gene Nqo1, and this was associated with minimal histologic injury at late timepoints. Kidneys exposed to severe injury failed to upregulate Nqo1, and this was associated with the development of chronic injury and fibrosis. Similarly, HK-2 cells exposed to mild stress conditions using nutrient replete media with CoCl₂ led to Nqo1 upregulation, but cells exposed to nutrient deficient conditions with CoCl₂ did not show Nqo1 induction. HIF-1α appeared to exert a negative effect on Nrf2 since HIF-1α knockdown enhanced Nqo1 expression. HIF-1α activation also suppressed Nrf2 nuclear localization in nutrient deficient conditions.

Conclusion

Our data suggest there is a threshold of severity at which AKI leads to the development of progressive CKD, and disparate outcomes may be partly determined by Nrf2 activity. Also, we demonstrate differential regulation of Nrf2 by HIF activation in mild and severe injury conditions. Overall, our results show that there is an association between Nrf2 and the HIF system that may determine the long-term outcome of the kidney.

Funding

• Other NIH Support