Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney

Song, Young Rim; You, Sun Jin; Lee, Yun Mi; Chin, Ho-Jun; Chae, Dong Wan; Oh, Yun Kyu; Joo, Kwon Wook; Han, Jin Suk; Na, Ki Young

doi:10.1093/ndt/gfp454

Cited by 129 publications

(99 citation statements)

References 47 publications

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“…This is consistent with the findings of a previous genetic study showing lower levels of ROS production and mitochondrial oxidative damage in muscle cells from PHD-deficient mice (47). In inflammatory bowel disease and chronic kidney failure, DMOG reduced secretion of proinflammatory cytokines, macrophage infiltration, and oxidative stress (48,49). Furthermore, in PHD2-haplodeficient mice, HIF-1 activity normalized blood vessel maturation and oxygen supply (50).…”

Section: Discussionsupporting

confidence: 89%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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Section: Discussionsupporting

confidence: 89%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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“…25 The finding that chronic HIF activation reduced proteinuria is in line with previous studies. Song et al 26 recently showed that HIF activation halted progression of proteinuria in a 27 reported that HIF activation by cobalt reduced renal expressions of TGF-b, connective tissue growth factor, and NADPH oxidase as well as reduced proteinuria, tubulointerstitial damage, and peritubular capillary loss in experimental type 2 diabetes. Indeed, tubulointerstitial fibrosis is a reliable marker for progression of kidney disease, and it is, therefore, interesting that HIF activation ameliorated fibrosis development in the diabetic kidney.…”

Section: Discussionmentioning

confidence: 99%

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Nordquist¹,

Friederich‐Persson²,

Fasching³

et al. 2015

Journal of the American Society of Nephrology

174

145

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Hyperglycemia results in increased oxygen consumption and decreased oxygen tension in the kidney. We tested the hypothesis that activation of hypoxia-inducible factors (HIFs) protects against diabetes-induced alterations in oxygen metabolism and kidney function. Experimental groups consisted of control and streptozotocin-induced diabetic rats treated with or without chronic cobalt chloride to activate HIFs. We elucidated the involvement of oxidative stress by studying the effects of acute administration of the superoxide dismutase mimetic tempol. Compared with controls, diabetic rats displayed tissue hypoxia throughout the kidney, glomerular hyperfiltration, increased oxygen consumption, increased total mitochondrial leak respiration, and decreased tubular sodium transport efficiency. Diabetic kidneys showed proteinuria and tubulointerstitial damage. Cobalt chloride activated HIFs, prevented the diabetes-induced alterations in oxygen metabolism, mitochondrial leak respiration, and kidney function, and reduced proteinuria and tubulointerstitial damage. The beneficial effects of tempol were less pronounced after activation of HIFs, indicating improved oxidative stress status. In conclusion, activation of HIFs prevents diabetesinduced alteration in kidney oxygen metabolism by normalizing glomerular filtration, which reduces tubular electrolyte load, preventing mitochondrial leak respiration and improving tubular transport efficiency. These improvements could be related to reduced oxidative stress and account for the reduced proteinuria and tubulointerstitial damage. Thus, pharmacologic activation of the HIF system may prevent development of diabetic nephropathy.

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“…Beneficial effects of HIF-stabilizing therapy have been found for a wide variety of ischemic disorders, such as myocardial and cerebral infarction or chronic kidney failure (48)(49)(50). An important focus of future research will be to specify the therapeutic targets of nonspecific pan-PHD inhibitors like DMOG to develop more specific, targeted drugs.…”

Section: Discussionmentioning

confidence: 99%

Hydroxylase Inhibition Abrogates TNF-α–Induced Intestinal Epithelial Damage by Hypoxia-Inducible Factor-1–Dependent Repression of FADD

Hindryckx

Vos

Jacques

et al. 2010

The Journal of Immunology

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Hydroxylase inhibitors stabilize hypoxia-inducible factor-1 (HIF-1), which has barrier-protective activity in the gut. Because the inflammatory cytokine TNF-α contributes to inflammatory bowel disease in part by compromising intestinal epithelial barrier integrity, hydroxylase inhibition may have beneficial effects in TNF-α–induced intestinal epithelial damage. The hydroxylase inhibitor dimethyloxalylglycin (DMOG) was tested in a murine model of TNF-α–driven chronic terminal ileitis. DMOG-treated mice experienced clinical benefit and showed clear attenuation of chronic intestinal inflammation compared with that of vehicle-treated littermates. Additional in vivo and in vitro experiments revealed that DMOG rapidly restored terminal ileal barrier function, at least in part through prevention of TNF-α–induced intestinal epithelial cell apoptosis. Subsequent transcriptional studies indicated that DMOG repressed Fas-associated death domain protein (FADD), a critical adaptor molecule in TNFR-1-mediated apoptosis, in an HIF-1α–dependent manner. Loss of this FADD repression by HIF-1α-targeting small interfering RNA significantly diminished the antiapoptotic action of DMOG. Additional molecular studies led to the discovery of a previously unappreciated HIF-1 binding site in the FADD promoter, which controls repression of FADD during hypoxia. As such, the results reported in this study allowed the identification of an innate mechanism that protects intestinal epithelial cells during (inflammatory) hypoxia, by direct modulation of death receptor signaling. Hydroxylase inhibition could represent a promising alternative treatment strategy for hypoxic inflammatory diseases, including inflammatory bowel disease.

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Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney

Abstract: Activation of HIF by DMOG halted the progression of proteinuria and attenuated structural damage by preventing podocyte injury in the remnant kidney model. This renoprotection was accompanied by a reduction of oxidative stress, inflammation and fibrosis.

Cited by 129 publications

References 47 publications

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Activation of Hypoxia-Inducible Factors Prevents Diabetic Nephropathy

Hydroxylase Inhibition Abrogates TNF-α–Induced Intestinal Epithelial Damage by Hypoxia-Inducible Factor-1–Dependent Repression of FADD

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