Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Bolisetty, Subhashini; Traylor, Amie M.; Kim, Jung-Hyun; Joseph, R; Ricart, Karina; Landar, Aimee; Agarwal, Anupam

doi:10.1681/asn.2010030238

Cited by 143 publications

(140 citation statements)

References 50 publications

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“…It has previously been demonstrated that the overexpression of HO-1 reduces cisplatin-induced excessive autophagy in proximal tubule cells (3). In accordance with this previous finding, the current results further demonstrated that the pharmacological activation of HO-1 inhibits external oxidative stress-mediated autophagy in glomerular mesangial cells; however the inactivation of HO-1 exacerbates the autophagic response.…”

Section: Discussionsupporting

confidence: 92%

“…Due to its beneficial effects, including oxidative stress relief and the inhibition of cell apoptosis, HO-1 has previously been proposed as a potential therapeutic target for ischemia/reperfusion or hypertension-induced glomerular injuries (2,3), and diabetic retinopathy (4). HO-1 has also been considered a potential biomarker of acute kidney injury (5).…”

Section: Introductionmentioning

confidence: 99%

“…In renal pathology (15), HO-1 inhibits autophagy in acute kidney injury and functions as an established therapeutic target for renal diseases (3). However, the regulatory mechanism through which HO-1 inhibits autophagy remains unclear (7).…”

Section: Introductionmentioning

confidence: 99%

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Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Wang

et al. 2016

Molecular Medicine Reports

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Abstract.Increasing evidence has demonstrated that the activation of heme oxygenase (HO)-1 reduces autophagy stimulated by oxidative stress injury, in which the supraphysiological production of reactive oxygen species (ROS) is detected. However, the potential mechanism underlying this effect remains unclear. The present study aimed to investigate the function of HO-1 activation in the regulation of autophagy in glomerular mesangial cells subjected to H 2 O 2 -induced oxidative stress injury. The results demonstrated that the HO-1 agonist, hemin, reduces the LC3 protein level, which was enhanced by H 2 O 2 treatment. Furthermore, hemin-activated HO-1 may function as a regulator of oxidative stress-induced autophagy in a dose-dependent manner. Pharmacological activation of c-Jun N-terminal kinase (JNK) inhibited the effect of hemin, indicating that the JNK signaling pathway is associated with the mechanism of HO-1 in impeding excessive autophagy. In addition to successfully alleviating H 2 O 2 -induced oxidative stress and cellular apoptosis, hemin-activated HO-1 may provide cytoprotection against rapamycin, a specific autophagy agonist. The present result suggested the inhibitory action of HO-1 in the avoidance of a potentially enhanced linkage between autophagy and apoptosis, particularly in the setting of excessive ROS. Therefore, enhancing the intracellular activity of HO-1 may assist the crosstalk between oxidative stress, autophagy and apoptosis, and represent a novel therapeutic strategy for renal ischemic disease. IntroductionPrevious investigation has demonstrated that heme oxygenase (HO), particularly the stress-responsive isoenzyme HO-1, exhibits vital regulatory functions in renal processes under pathophysiological conditions (1). Due to its beneficial effects, including oxidative stress relief and the inhibition of cell apoptosis, HO-1 has previously been proposed as a potential therapeutic target for ischemia/reperfusion or hypertension-induced glomerular injuries (2,3), and diabetic retinopathy (4). HO-1 has also been considered a potential biomarker of acute kidney injury (5). Multiple mechanisms may be involved in the protective effects of activated HO-1 (6). In a previous study, the effect of HO-1 in autophagy, an apoptosis-associated biological process, was also investigated, and an implication of the comprehensive understanding of the protective mechanisms of HO-1 was provided (7).Autophagy has been widely studied in the last decade (8). The mechanism of autophagy has been elucidated based on pathophysiology to understand human biology and disease (9-11). Autophagy must be reconsidered not only as a self-degrading strategy for cell survival, but also as a type of dynamic and systematic re-organization of cellular materials and energy (12). As such, an appropriate intervention strategy effecting autophagy may direct cellular materials and energy flow to intended processes in order to result in the alleviation of diseases. Therefore, targeting autophagy may be a non-limiting therapeutic strategy ...

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Wang

et al. 2016

Molecular Medicine Reports

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“…65 Moreover, deletion of autophagy genes, including Atg5 and Atg7, blocks autophagy induction in AKI and enhances kidney injury. [66][67][68] It remains unclear as to how autophagy is activated in AKI. p53 inhibitors can partially suppress cisplatin-induced autophagy in renal tubular cells, 67 suggesting a role of p53 in triggering autophagy.…”

Section: Receptorsmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

Self Cite

175

151

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In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

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“…Studies have indicated that upregulation of HMOX-1 is correlated with the inhibition of autophagy (19,20). Autophagy, which describes the process of cellular self-digestion, is considered to be a cytoprotective response, which may occur following the withdrawal of growth factors or under stressful conditions (21).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

Zhu

et al. 2015

Oncology Letters

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Abstract. Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer. IntroductionBreast cancer is the most frequently diagnosed cancer amongst females and the second most common cause of cancer-related mortality among women (1). One third of novel cancer diagnoses in females are breast cancer and a total of one in eight women will be diagnosed with breast cancer, with a lifetime risk of mortality due to breast cancer of 3.4% (1). Chemotherapy is one of the major systemic therapies available for the treatment of breast cancer. A recent meta-analysis of the outcome of 100,000 patients with breast cancer, confirmed the benefit of cyclophosphamide-, methotrexate-and fluorouracil-therapies and anthracycline-based therapies with absolute reduction of mortalities of 6.2 and 6.5%, respectively, at 10 years (2). Despite progress in the improvement of chemotherapeutic strategies, the ability to treat advanced breast cancer remains poor, mainly due to the chemoresistance of cancer cells to standard chemotherapy. Numerous anti-apoptotic and cytoprotective pathways have been associated with the chemoresistance of cancer cells (3,4).Heme oxygenase (HMOX) is a microsomal enzyme, which catalyzes the initial, rate-limiting step in the degradation of heme, and has a crucial role in the recycling of iron (5). The enzymatic activity of HMOX also produces CO, ferrous iron and biliverdin. Thus, HMOX is able to reduce oxidative stress, attenuate inflammatory responses and lower the rate of apoptosis (6). HMOX-1, an isoform of HMOX, may be induced in response to cellular stress and diverse oxidative stimuli (7). HMOX-1 is frequently overexpressed in a range of cancers, including hepatoma, prostate cancer, melanoma and brain tumors (8-11). HMOX-1 promotes proliferation in human melanoma and pancreatic cancer cell lines (10,12). As HMOX-1 is a potent inducer of vascular endothelial growth factor (VEGF), a crucial factor involved in tumor angiogenesis, it has also been recognized to stimulate angiogenesis and thus support tumor progression (13). Additionally, overexpression of...

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Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Cited by 143 publications

References 50 publications

Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Heme oxygenase-1 protects H2O2-insulted glomerular mesangial cells from excessive autophagy

Cellular and Molecular Mechanisms of AKI

Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

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