Control of Renal Central Carbon Metabolism  by Heme Oxygenase-1
Metabolic adaptation refers to the regulation of cellular metabolism to prevent tissue dysfunction in response to different forms of stress. Heme, an iron-containing porphyrin, is indispensable for oxygen transport and for the activity of hemoproteins such as catalases. Cytotoxic “labile” heme is readily degraded by two distinct heme oxygenases (HO). The conditional deletion of Hmox-1, the gene encoding the inducible heme-degrading enzyme heme oxygenase (HO)-1, impairs metabolic adaptation to malaria and to polymicrobial infection. Embryonic deficiency in HO-1 is partially lethal in mice and surviving animals show progressive chronic inflammatory disease making them an unsuitable model to study metabolic adaptation. Here we found that mice with an inducible deletion of Hmox1 (Hmox1R26?/?) but not control mice rapidly succumbed to sterile hemolytic stress. Mortality was associated with heme-driven kidney failure, hypoglycemia, and disruption of adaptive thermoregulation. RNA sequencing and targeted metabolomics combined with data-driven in silico metabolic modeling revealed that failed renal metabolic adaptation is driven by altered oxidative phosphorylation and impaired pentose phosphate pathway. Heme-induced kidney failure and mortality in Hmox1R26?/? mice was not prevented with impairment of the inflammatory response, nor with antioxidants. Our results emphasize the critical importance of Hmox1 expression in hemolytic stress leading to acute kidney injury and death. Overall design: To investigate the relevance of kidney Hmox1 expression during hemin stimulation, we utilized and inducible whole body KO for Hmox1 ( Rosa26Cre-ERT2 Hmox1). We then performed gene expression profile analysis using RNA-seq of 4 different time points . Comparative gene expression analysis of RNA-Seq data for WT mice vs. Hmox1 KO at each different time point.