Phenotypic characterization of a novel HO-1 depletion model in the rat

Abstract

Although the protective role of HO-1 induction in various forms of kidney disease is well established, mechanisms other than heme catabolism to biliverdin, bilirubin and carbon monoxide have recently been identified. Unraveling these mechanisms requires the generation of appropriate animal models. The present study describes the generation of a HO-1 deficient Hmox1 rat model and characterizes its renal and extrarenal phenotype. Hmox1 rats had growth retardation and splenomegaly compared to their Hmox1 littermates. Focal segmental glomerulosclerosis-type lesions and interstitial inflammatory infiltrates were prominent morphologic findings and were associated with increased blood urea nitrogen, serum creatinine and albuminuria. There was no increase in iron deposition in glomeruli, tubules or interstitium. Iron deposition in spleen and liver was reduced. Electron microscopic examination of glomeruli revealed edematous podocytes with scant areas of foot process effacement but otherwise well preserved processes and slit-diaphragms. Of the filtration barrier proteins examined, β-catenin expression was markedly reduced both in glomeruli and extrarenal tissues. Since the rat is the preferred laboratory animal in experimental physiology and pathophysiology, the rat model of HO-1 deficiency may provide a novel tool for investigation of the role of this enzyme in renal function and disease.

Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

“…A rat model of HO-1 deficiency was recently described by Atsaves et al [30]. Sprague-Dawley rats were employed in the study to reveal the role of HO-1 in various forms of kidney disease.…”

Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

“…While glomerular lesions were anecdotal in the mouse model, Atsaves et al found an increase in mesangial matrix and focal and segmental glomerulosclerotic lesions in Hmox1 −/− rats. These morphological findings were associated with increased blood urea nitrogen, serum creatinine and albuminuria, but interestingly there was no increase in iron deposits in the glomeruli, tubules or interstitium [20].…”

“…Kidney biopsies revealed increased mesangial proliferation and focal thickening of the capillary loops by light microscopy, and endothelial detachment in the glomerular capillary by electron microscopy [17,18]. Renal injuries were also present in both animal models invalidated for HMOX1, with some differences apparent between the mouse [19] and rat models [20]. In Hmox1 −/− mice, lack of functional heme oxygenase was responsible for enhanced susceptibility to oxidative stress [19], decreased hemophagocytosis of senescent red blood cells by tissue macrophages, increased hemolysis and redistribution of iron from splenic and hepatic macrophages to hepatocytes and renal proximal tubule cells [21].…”

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

“…Certain molecules that regulate metabolic functions in many cell types, including in immune cells, have been analyzed using genetically modified rats. Transgenic rats for heme oxygenase-1 (HO-1) under the control of the ubiquitous H-2Kb promoter (Braudeau et al, 2003) and HO-1 KO rats (Atsaves et al, 2017) have facilitated dissection of different aspects of HO-1 effects, particularly in kidney, where the lesions observed in rats differ from those in mice.…”