Abstract: TH-PO108
The Role of Hemopexin as a Protectant Against AKI
Session Information
- AKI: Inflammation, New Technologies, Omics
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Croatt, Anthony J., Mayo Clinic , Rochester, Minnesota, United States
- Belcher, John D., University of Minnesota, Minneaplis, Minnesota, United States
- Grande, Joseph P., Mayo Clinic , Rochester, Minnesota, United States
- Regan, Raymond F., Thomas Jefferson University, Philadelphia, Pennsylvania, United States
- Vercellotti, Gregory M., University of Minnesota, Minneaplis, Minnesota, United States
- Nath, Karl A., Mayo Clinic , Rochester, Minnesota, United States
Background
In ischemic and nephrotoxic acute kidney injury (AKI), renal heme content and plasma heme levels are increased. Heme is prooxidant, proinflammatory, and nephrotoxic. Levels of heme are restrained by degradation by heme oxygenase (HO) and by the binding of heme to hemopexin (HPX). HPX is also anti-inflammatory. We questioned whether induction of HPX occurs in AKI and its functional significance.
Methods
Renal HPX mRNA and protein expression was assessed by RT-PCR and western analysis respectively. Renal function was evaluated by serum creatinine and blood urea nitrogen (BUN). Multiple AKI models were employed, including glycerol-induced, heme protein-mediated AKI, and AKI induced by either acute ischemia, endotoxin, or hemoglobin.
Results
HPX mRNA and protein were vigorously induced in the kidney exposed to hemoglobin, along with the receptor for the HPX-heme complex CD91. We thus examined the effect of glycerol-induced, heme protein-mediated AKI in HPX+/+ and HPX-/- mice. Renal function was comparable in these mice prior to the administration of hypertonic glycerol and on days 1 and 2 after the induction of AKI. However, HPX-/- mice as compared to HPX+/+ mice exhibited significantly higher BUN at day 3 (166 ± 24 vs 104 ± 17 mg/dl) and day 4 (142 ± 23 vs 82 ± 11 mg/dl) following the induction of AKI; similarly, serum creatinine values were also higher on day 3 (1.4 ± 0.2 vs 0.8 ± 0.1 mg/dl) and day 4 (1.2 ± 0.2 vs 0.7 ± 0.1 mg/dl) in HPX-/- mice compared with HPX+/+ mice. In ischemia-induced AKI, HPX mRNA and protein are also vigorously induced in the kidney, along with CD91. However, no differences were observed in renal function in HPX+/+ and HPX-/- mice at days 1 and 2 following ischemia. No differences in renal function were observed in HPX+/+ and HPX-/- mice at days 1 and 2 following endotoxin-induced AKI, and at days 1 and 7 following hemoglobin-induced AKI.
Conclusion
HPX is significantly induced in both nephrotoxic and ischemic models of AKI. A beneficial, functional effect of such induction is observed in glycerol-induced, heme protein-mediated AKI, but only in the recovery phase of such AKI. We suggest that when HO-1, the potent, broad-based protectant in AKI, is intact, HPX provides a secondary backup system for guarding against heme toxicity.
Funding
- NIDDK Support