Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

Liu, Jing; Wei, Qingqing; Guo, Chunyuan; Dong, Guie; Liu, Yu; Tang, Chengyuan; Dong, Zheng

doi:10.3390/ijms18050950

Cited by 97 publications

(111 citation statements)

References 144 publications

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“…HIF-2α seems to be a hypoxia-specific marker as it is detectable in hypoxia in various organs and tissues. Lui Jing et al had found HIF-2α in patients with ischemic kidney damage and showed the critical value of HIF-2α as a marker of hypoxia [22]. Similarly, HIF-2α could be detected through 1-4 hours in serum after inhalation of CO.…”

Section: Discussionmentioning

confidence: 98%

The use of serum hypoxia-inducible factor two alpha levels and diagnostic values in adult carbon monoxide poisoning

Altıntop¹,

Tatlı²,

Karakükçü³

et al. 2018

Med-Science

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Carbon monoxide poisoning (COP) is a life-threatening intoxication which should be interfered immediately to be prevented from serious damages. The effect of carbon monoxide (CO) in the body at the cell level is mediated by a CO-releasing molecule. This molecule results in heme degradation via heme oxygenase. Because of the high affinity of CO on heme, many enzymes with biological signal transduction cause heme protein increase. Universally, this signal activation with similar enzymes and mechanisms are used in COP. The most widely used test is Carboxyhaemoglobin (COHb) in serum. The COHb is used as a standard parameter in the diagnosis of COP. COHb levels, are high after CO poisoning and decrease rapidly with oxygen therapy in the first four hours. So COHb is insufficient to demonstrate chronic ischemic damage of hypoxia. Hypoxia-inducible factors (HIFs) are the master regulators of oxygen homeostasis. The best known HIF isoforms in the literature are HIF-1ɑ and HIF-2ɑ. Recently, more data have found about selective HIF-2ɑ responsive genes and indicate the importance of this isoform in hypoxic gene regulation. The present study purposed to determine the change in HIF-2ɑ values in adult patients in diagnosing COP. A significant statistical correlation was found between (p=0.05) serum HIF-2ɑ levels and the first COHb level. HIF-2ɑ levels at 4th hour in COP patients were significantly higher like first COHb. HIF-2ɑ levels can be used as a new biomarker in long-term for monitoring COP patients.

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Section: Discussionmentioning

confidence: 98%

The use of serum hypoxia-inducible factor two alpha levels and diagnostic values in adult carbon monoxide poisoning

Altıntop¹,

Tatlı²,

Karakükçü³

et al. 2018

Med-Science

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“…In the kidney, podocytes, distal tubules, collecting ducts, and proximal tubules produce VEGF, which plays an important role in the development and integrity of the nephron and renal interstitium. 28,30) VEGF is mainly regulated by HIF-1 at the transcriptional level and the activity of HIF-1 is dependent on the availability of the HIF-1α subunit. It is still controversial whether HIF-1α is pro-fibrotic or anti-fibrotic due to its different roles in different renal cells.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Ameliorates Chronic Renal Failure in 5/6 Nephrectomized Rats by Regulation of the mTOR/HIF-1α/VEGF Signaling Pathway

He¹,

Lang²,

Cheng³

et al. 2019

Biological & Pharmaceutical Bulletin

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Previous studies implicated the mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway in renal fibrosis and found that curcumin could suppress the expression of mTOR. Therefore, the aim of the present study was to investigate the therapeutic effects of curcumin against chronic renal failure (CRF) in a rat model induced by 5/6 nephrectomy through inhibition of mTOR/HIF-1α/VEGF signaling. A total of 70 male Sprague-Dawley rats were divided into seven groups: a sham group, a CRF group, and five treatment groups. Except for the sham rats, all rats underwent 5/6 nephrectomy to induce CRF. The 5/6 nephrectomized rats received treatment with curcumin vehicle, everolimus vehicle, curcumin, everolimus, or the combination of curcumin and everolimus. Everolimus, a specific inhibitor of mTOR, was used as a positive control. At the end of treatment, blood biochemical indexes, proteinuria and the kidney index were detected. Moreover, histological change was examined by hematoxylin and eosin staining, and protein expression levels were detected by Western blotting. The blood biochemical indexes, proteinuria, and kidney index were increased in the CRF group as compared to the sham group, which was accompanied by marked activation of the mTOR/HIF-1α/VEGF pathway. However, curcumin, as well as everolimus, restored or ameliorated these changes. These results indicate that activation of the mTOR/HIF-1α/VEGF signaling pathway plays an important role in the occurrence and development of CRF, and that curcumin has renoprotective effects by blocking activation of this pathway.

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“…The most notable of these PHD inhibitors are Roxadustat (FG-4592), Vadadustat (AKB-6548), Daprodustat (GSK1278863), Desidustat (ZYAN-1), and Molidustat (Bay 85-3934), all of which have been developed as orally acting drugs for the treatment of anemia, with the expectation that they will also improve kidney function. HIF can crosstalk with multiple profibrotic signaling pathways, including TGF-β, Notch, NF-κB, and PI3K/Akt pathways, to further regulate renal fibrosis (25 stimulation of stress responses, including tubular epithelial autophagy (ref. 16 and Figure 1).…”

Section: Failed Tubule Cell Repairmentioning

confidence: 99%