Journal
ANTIOXIDANTS
Volume 11, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/antiox11101888
Keywords
acute kidney injury; heme oxygenase; cisplatin nephrotoxicity; small-molecule drugs; high-throughput screen
Funding
- NIH-NIDDK [P30 DK079337, R01 DK059600, R01 DK118932]
- Alabama Drug Discovery Alliance
- PRIME [T32 DK116672]
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Acute kidney injury is a major health concern with no current effective treatments. This study identifies small-molecule inducers of HO-1 as potential therapeutic candidates for AKI.
Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase 1/2 level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an E-max >= 70% of 5 mu M hemin and EC50 <10 mu M. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI.
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