Pharmacological Induction of Heme Oxygenase-1 Inhibits iNOS and Oxidative Stress in Renal Ischemia-Reperfusion Injury (original) (raw)
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General physiology and biophysics, 2018
The current study investigated the effect of upregulation of heme oxygenase 1 (HO-1) by cobalt protoporphyrin (CoPP) on renal dysfunctions in renal ischemia/reperfusion (I/R) injury and its underlying mechanisms. 72 male Sprague Dawley rats were divided into 4 groups: sham group, ischemic group (left 45-min renal ischemia), CoPP-before group (as ischemic group with CoPP 20 mg/kg 30 min before ischemia) and CoPP-after group (as ischemic group with CoPP 20 mg/kg 20 min after ischemia). Serum creatinine, urea and TGF-β1 and markers of redox state (MDA, SOD, GSH and CAT), nitric oxide (NO), TGF-β1 and HO-1 in kidney tissues were measured. Serum creatinine and urea levels were significantly increased in ischemic group and attenuated in CoPP-treated groups (p < 0.05). Also, markers of redox state showed significant deteriorations in ischemic group which were improved significantly in CoPP-treated groups (p < 0.05). HO-1 expression in kidney tissues showed significant increase in isc...
Kidney International, 2007
Heme oxygenase-1 may exert cytoprotective effects. In this study we examined the sensitivity of heme oxygenase-1 knockout (HO-1 −/− ) mice to renal ischemia by assessing glomerular filtration rate (GFR) and cytokine expression in the kidney, and inflammatory responses in the systemic circulation and in vital extrarenal organs. Four hours after renal ischemia, the GFR of HO-1 −/− mice was much lower than that of wild-type mice in the absence of changes in renal blood flow or cardiac output. Eight hours after renal ischemia, there was a marked induction of interleukin-6 (IL-6) mRNA and its downstream signaling effector, phosphorylated signal transducer and activator of transcription 3 (pSTAT3), in the kidney, lung, and heart in HO-1 −/− mice. Systemic levels of IL-6 were markedly and uniquely increased in HO-1 −/− mice after ischemia as compared to wild-type mice. The administration of an antibody to IL-6 protected against the renal dysfunction and mortality observed in HO-1 −/− mice following ischemia. We suggest that the exaggerated production of IL-6, occurring regionally and systemically following localized renal ischemia, in an HO-1-deficient state may underlie the heightened sensitivity observed in this setting.
Renal Response to Tissue Injury Lessons from Heme Oxygenase-1 Gene Ablation and Expression
Journal of the American Society of Nephrology, 2000
Heme oxygenase-1 (HO-1) is a microsomal enzyme involved in the degradation of heme, resulting in the generation of biliverdin, iron, and carbon monoxide. Recent attention has focused on the biologic effects of product(s) of this enzymatic reaction that have important antioxidant, anti-inflammatory, and cytoprotective functions. Induction of HO-1 occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli, including heme, hydrogen peroxide, cytokines, growth factors, heavy metals, nitric oxide, and oxidized LDL. HO-1 has been implicated in several clinically relevant disease states, including transplant rejection, hypertension, acute renal injury, atherosclerosis, and others. Previous studies indicate a protective role for HO-1 in heme and non-heme-mediated models of
The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury
American Journal of Physiology-Renal Physiology, 2004
Heme oxygenases (HOs) catalyze the rate-limiting step in heme degradation, resulting in the formation of iron, carbon monoxide, and biliverdin, the latter of which is subsequently converted to bilirubin by biliverdin reductase. Recent attention has focused on the biological effects of product(s) of this enzymatic reaction, which have important antioxidant, anti-inflammatory, and cytoprotective functions. Two major isoforms of the HO enzyme have been described: an inducible isoform, HO-1, and a constitutively expressed isoform, HO-2. A third isoform, HO-3, closely related to HO-2, has also been described. Several stimuli implicated in the pathogenesis of renal injury, such as heme, nitric oxide, growth factors, angiotensin II, cytokines, and nephrotoxins, induce HO-1. Induction of HO-1 occurs as an adaptive and beneficial response to these stimuli, as demonstrated by studies in renal and non-renal disease states. This review will focus on the molecular regulation of the HO-1 gene in ...
Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury
Scientific Reports, 2017
Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1 M-KO), littermate (LT), and wildtype (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1 M-KO exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1 M-KO mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b + F4/80 lo subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1 + CD11b + F4/80 lo myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1 M-KO mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation. Ischemia-reperfusion injury (IRI) is inherent to renal transplantation and leads to delayed graft function (DGF) of transplanted kidneys from deceased donors in up to 20 to 50% of cases 1, 2. Later, DGF contributes to the reduced longevity of the kidney allografts, notably because of a higher risk of acute and chronic rejection 3, 4. Basically, IRI is a two-phase phenomenon, including ischemia in the donor and reperfusion injury in the recipient. It combines major ischemia-induced cell stress, significant burst of free radicals, and intense inflammatory immune responses that lead to extensive cell injury, necrosis, and late interstitial fibrosis of the kidney allograft 1, 5. Today, the increasing demand for renal allografts implies more frequent use of organs issued from extended criteria donors and this change leads to an increased risk of DGF 6, 7. So far, there is no specific treatment of IRI and a better understanding of underlying mechanisms might lead to a better prevention of DGF and successful transplantations even with transplant from extended criteria donors. Several natural cellular mechanisms can confer resistance against IRI, including the ubiquitous heme oxygenase (HO) cytoprotective pathway 8. Upon cellular stress, the expression of HO isoform 1 (HO-1, encoded by Hmox1) is significantly induced. The main action of HO-1 is the enzymatic degradation of free heme, a source of reactive species massively released during IRI. HO-1 metabolizes free heme into carbon monoxide, biliverdin that can both provide resistance against IRI 8. Interestingly, HO-1-deficient mice exhibit severe acute kidney injury (AKI) and death upon renal IRI 9, 10. In humans, reduced capacity of the donor to express HO-1 was associated
Protective effect of heme oxygenase induction in ischemic acute renal failure
Critical Care Medicine, 2000
Estrogen-induced cholestasis is characterized by impaired hepatic uptake and biliary bile acids secretion because of changes in hepatocyte transporter expression. The induction of heme oxygenase-1 (HMOX1), the inducible isozyme in heme catabolism, is mediated via the Bach1/ Nrf2 pathway, and protects livers from toxic, oxidative and inflammatory insults. However, its role in cholestasis remains unknown. Here, we investigated the effects of HMOX1 induction by heme on ethinylestradiol-induced cholestasis and possible underlying mechanisms. Wistar rats were given ethinylestradiol (5 mg/kg s.c.) for 5 days. HMOX1 was induced by heme (15 lmol/kg i.p.) 24 hrs prior to ethinylestradiol. Serum cholestatic markers, hepatocyte and renal membrane transporter expression, and biliary and urinary bile acids excretion were quantified. Ethinylestradiol significantly increased cholestatic markers (P ≤ 0.01), decreased biliary bile acid excretion (39%, P = 0.01), down-regulated hepatocyte transporters (Ntcp/Oatp1b2/Oatp1a4/Mrp2, P ≤ 0.05), and up-regulated Mrp3 (348%, P ≤ 0.05). Heme pre-treatment normalized cholestatic markers, increased biliary bile acid excretion (167%, P ≤ 0.05) and up-regulated hepatocyte transporter expression. Moreover, heme induced Mrp3 expression in control (319%, P ≤ 0.05) and ethinylestradiol-treated rats (512%, P ≤ 0.05). In primary rat hepatocytes, Nrf2 silencing completely abolished heme-induced Mrp3 expression. Additionally, heme significantly increased urinary bile acid clearance via up-regulation (Mrp2/Mrp4) or down-regulation (Mrp3) of renal transporters (P ≤ 0.05). We conclude that HMOX1 induction by heme increases hepatocyte transporter expression, subsequently stimulating bile flow in cholestasis. Also, heme stimulates hepatic Mrp3 expression via a Nrf2dependent mechanism. Bile acids transported by Mrp3 to the plasma are highly cleared into the urine, resulting in normal plasma bile acid levels. Thus, HMOX1 induction may be a potential therapeutic strategy for the treatment of ethinylestradiol-induced cholestasis.