Abstract: PO0363
Heme Oxygenase 1 Is a Key Player in Arsenical-Induced AKI
Session Information
- AKI: Mechanisms of Injury
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Traylor, Amie, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Srivastava, Ritesh, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Esman, Stephanie, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Khan, Jasim, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Zmijewska, Anna Alicja, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Mathew, Bini, Southern Research, Birmingham, Alabama, United States
- Black, Laurence Marie, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Suto, Mark J., Southern Research, Birmingham, Alabama, United States
- Athar, Mohammad, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Agarwal, Anupam, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background
Arsenicals, such as Lewisite, are a class of warfare vesicants that cause immediate and painful blistering of the skin and mucous membranes upon contact. Systemic absorption of arsenicals results in “Lewisite shock,” which is characterized by hypovolemia due to capillary damage, and multi-organ dysfunction. There is an ongoing risk of exposure from arsenical weaponization, but accidental exposures from underground storage of these compounds in several countries including the US, Italy, Russia, and Japan also pose a risk. Molecular mechanisms of arsenical-induced injury involve oxidative and endoplasmic reticulum (ER) stress, inflammation, and cell death. We have previously reported that a single cutaneous exposure to arsencials causes acute kidney injury (AKI) in mice as evidenced by increased serum and urinary biomarkers of AKI. Intrarenal heme oxygenase-1 (HO-1), a protective anti-oxidant enzyme, is also upregulated as a response to injury in addition to ATF4 and CHOP, molecules involved in regulation of ER stress and cell death.
Methods
To interrogate the precise role of HO-1 in arsenical-induced AKI, we exposed HO-1 knockout mice (HO-1-/-) and wild-type controls to phenylarsine oxide (PAO), an analog of Lewisite that is commonly used due to the restricted use of this vesicant. Employing in vitro techniques, we further tested the efficacy of a novel small molecule inducer of HO-1, SR-37618 after PAO treatment.
Results
Our data show that HO-1 deficiency results in worse kidney damage post-PAO exposure, suggesting it is a targetable enzyme for intervention. Utilizing a novel small molecule inducer of HO-1 created in collaboration with Southern Research, we demonstrate that 1 hour pre-treatment with SR-37618 diminishes PAO-induced ATF4 and CHOP expression in HEK-293 cells.
Conclusion
While further studies to assess the efficacy of SR-37618 in mouse models are ongoing, the data presented here provide evidence that HO-1 induction by SR-37618 is protective against arsenical-induced AKI. Moreover, small molecule inducers of HO-1 could potentially serve as a novel therapeutic for intervention in other forms of AKI.
Funding
- NIDDK Support