title: Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury.
abstract: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. The beneficial effects of HO-1 expression are not merely due to degradation of the pro-oxidant heme but are also credited to the by-products that have potent, protective effects, including antioxidant, anti-inflammatory, and prosurvival properties. This is well reflected in the preclinical animal models of injury in both renal and nonrenal settings. However, excessive accumulation of the by-products can be deleterious and lead to mitochondrial toxicity and oxidative stress. Therefore, use of the HO system in alleviating injury merits a targeted approach. Based on the higher susceptibility of the proximal tubule segment of the nephron to injury, we generated transgenic mice using cre-lox technology to enable manipulation of HO-1 (deletion or overexpression) in a cell-specific manner. We demonstrate the validity and feasibility of these mice by breeding them with proximal tubule-specific Cre transgenic mice. Similar to previous reports using chemical modulators and global transgenic mice, we demonstrate that whereas deletion of HO-1, specifically in the proximal tubules, aggravates structural and functional damage during cisplatin nephrotoxicity, selective overexpression of HO-1 in proximal tubules is protective. At the cellular level, cleaved caspase-3 expression, a marker of apoptosis, and p38 signaling were modulated by HO-1. Use of these transgenic mice will aid in the evaluation of the effects of cell-specific HO-1 expression in response to injury and assist in the generation of targeted approaches that will enhance recovery with reduced, unwarranted adverse effects.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Amie
authors.initials: A
authors.lastname: Traylor
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Reny
authors.initials: R
authors.lastname: Joseph
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Abolfazl
authors.initials: A
authors.lastname: Zarjou
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama; and Birmingham Veterans Administration Medical Center, Birmingham, Alabama agarwal@uab.edu.
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin; D004195:Disease Models, Animal; D005838:Genotype; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D010641:Phenotype; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D002945:Cisplatin
keywords: acute kidney injury; cisplatin; heme oxygenase-1; p38