Role of heme oxygenase-1 in endotoxemic acute renal failure

Abstract

The pathogenesis of septic acute renal failure (ARF) involves systemic vasodilation with compensatory upregulation of vasoconstrictors. This can lead to renal vasoconstriction and ARF. Heme oxygenase (HO) is the rate-limiting step in heme metabolism and produces carbon monoxide (CO) and biliverdin. HO-1 is an inducible form of the enzyme and is expressed in response to cell injury. It was hypothesized in endotoxemia, induction of HO-1 would lead to increased production of the vasodilator CO, lower blood pressure, and decrease renal function. The role of HO-1 was therefore examined in a mouse model of endotoxemia. One group of mice received LPS alone and were compared with mice that received LPS in addition to an inhibitor of HO-1, zinc protoporphyrin (ZnPP). Treatment of mice with LPS resulted in significant increases in the protein expression of HO-1 compared with controls treated with vehicle. Immunohistochemical analysis localized this upregulation to both the proximal and distal tubules as well as the vasculature. Hemodynamic studies were performed during endotoxemia and the mean arterial pressure (MAP) was found to be significantly higher in the HO-1 inhibitor-treated compared with vehicle-treated mice (78 +/- 3 vs. 64 +/- 2 mmHg, P < 0.01). It was found that the inhibitor group had higher renal blood flows (RBF) also during endotoxemia (1.8 +/- 0.2 vs. 0.68 +/- 0.1 ml/min, P < 0.01). Furthermore, when renal vascular resistance (RVR) was calculated, there was a significant decrease in RVR in the inhibitor group (43.5 +/- 3.4 vs. 95.9 +/- 11.3 mmHg.ml(-1).min(-1), P < 0.01). In concert with the hemodynamic data, glomerular filtration rate (GFR), as measured by inulin clearance, was higher in the HO inhibitor compared with the vehicle controls during endotoxemia (111.5 +/- 19.5 vs. 66.0 +/- 3.5 microl/min, P < 0.05). In summary, during endotoxemia ARF, inhibiting HO-1 with ZnPP resulted in the protection of renal function. The renal protection was associated with significantly improved systemic hemodynamics, less renal vasoconstriction, and a higher GFR.

Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1−/− Mice

“…The greater impairment of renal hemodynamics in LPStreated HO-1 Ϫ/Ϫ mice observed in the current study contrasts with conclusions based on the use of metalloporphyrin inhibitors of HO activity to evaluate the role of the HO system in determining the renal hemodynamic response to LPS. 38 In these latter studies, such inhibitors of HO activity, administered to LPS-treated wild-type mice, increased GFR and decreased RVR, 38 findings that are not consistent with those derived in the present study when LPS was administered to HO-1 Ϫ/Ϫ mice. Although the basis for these differences is uncertain at the present time, it is notable that metalloporphyrin inhibitors of HO activity may also affect other vasoactive systems besides HO, including nitric oxide synthase, guanylate cyclase, and atrial natriuretic peptides.…”

Heme oxygenase-1 induction contributes to renoprotection by G-CSF during rhabdomyolysis-associated acute kidney injury

“…To determine whether HO-1 induction contributed to the observed renoprotective effects of G-CSF, we examined the effects of ZnPP, a pharmacological inhibitor of HO-1 (15,25). RPTC cells were cultured for 3 days in the absence or presence of 500 ng/ml G-CSF for pretreatment.…”

Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

“…Septic shock is characterized by generalized systemic vasodilation and hypotension accompanied by vascular hyporesponsiveness, leading to multiple organ failure and death (8,9). Although systemic hypotension is often present, LPS-induced ARF is characterized by marked intrarenal vasoconstriction (10,11).…”