Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

Abstract

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney's filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1's functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1's role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

Keywords: heme; heme-oxygenase-1; hemolysis; ischemia reperfusion; kidney; rhabdomyolysis; toxicity.

Figure 1

Schematic view of kidney structures describing cortical and medullar compartments, components of glomerular basement membrane and tubular segments and structures. GBM: Glomerular basement membrane, TALH: Thick ascending loop of Henle (Created with BioRender.com).

Figure 2

Renal expression of HO1 (adapted from [27]). HO-1 staining in mouse kidneys in IF (A) and IHC (B). A- HO-1 (red) staining, vWF (green) staining, and colocalization on frozen kidney (x15) sections of mice, injected with PBS (upper panel) or heme as HO1 inducer (lower panel), studied by IF (A); B- HO-1 staining appears in brown on frozen kidneys sections of mice treated with PBS or heme. (C) HO-1 expression in human kidneys: hemosiderin deposits in human kidney biopsies evaluated by Perls’ coloration and HO-1 (brown) staining were performed by IHC. A normal protocol, kidney allograft biopsy performed 3 months after transplant was used as a negative control. Patients 1 and 2 suffered chronic hemolysis associated with prosthetic heart valves, and patient 3 carried the C3 mutation complicated with atypical hemolytic uremic syndrome (arrows indicate glomeruli).

Figure 3

Schematic description of HO-1 regulation in renal pathologies. Plain arrows: proved link, Dotted arrows: suspected link, AKI: acute kidney injury, SCA: sickle cell anemia, HUS: hemolytic uremic syndrom, PNH: paroxysmal nocturnal haemoglobinuria (Created with BioRender.com).