Myeloid HO-1 prevents kidney remote organ damage following renal ischemia-reperfusion injury
Renal ischemia-reperfusion injury (IRI) is an inherent process to kidney transplantation. The subsequent release of pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6) may induce a systemic inflammatory response, resulting in pro-inflammatory cells recruitment and remote organ damage. Several studies have already documented dysfunction of the lung, heart, liver, and brain following renal IRI. The heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with cytoprotective, antiapoptotic, and immunomodulatory properties, protects kidney from renal IRI when pharmacology induced before ischemia. The impact of HO-1 in the pathogenesis of distant organ injury has not been yet studied. We therefore investigated the role of HO-1 in the control of kidney remote organ damage following IRI.
Wild-type (WT) C57/Bl6 mice underwent bilateral renal IRI for 26 min. 4h or 24h after reperfusion, plasma and lungs were harvested. WT mice were treated with hemin 5 mg/kg (pharmacological inducer of HO-1) or saline 24h prior ischemia. Hemin-induced HO-1 and systemic cytokines expression were assessed by ELISA. Renal IRI was evaluated by plasma creatinine. Hepatic dysfunction was assessed by transaminases levels. Lung inflammation and pulmonary neutrophil influx were assessed by ELISA and immunostaining respectively.
In WT mice, hemin induces HO-1 expression and protects against renal IRI as attested by lower plasma creatinine compared to saline-treated mice. This renal protective effect of hemin pretreatment was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, a mitigated hepatic dysfunction and lung inflammation were found in hemin-treated mice.
Our results demonstrate that HO-1 spontaneously controls the magnitude of renal IRI and the subsequent systemic inflammation-induced remote organ damage. This HO-1-mediated protective pathway can be pharmacologically modulated by hemin administration. Therefore targeting HO-1 represents a promising approach to prevent the impact of IRI on renal transplants and distant organs.