{"id":90880,"date":"2016-07-06T04:29:23","date_gmt":"2016-07-06T04:29:23","guid":{"rendered":"http:\/\/healthmedicinet.com\/i\/hypoxia-and-hypoxia-inducible-factors-in-chronic-kidney-disease\/"},"modified":"2016-07-06T04:29:23","modified_gmt":"2016-07-06T04:29:23","slug":"hypoxia-and-hypoxia-inducible-factors-in-chronic-kidney-disease","status":"publish","type":"post","link":"http:\/\/healthmedicinet.com\/i\/hypoxia-and-hypoxia-inducible-factors-in-chronic-kidney-disease\/","title":{"rendered":"Hypoxia and hypoxia-inducible factors in chronic kidney disease"},"content":{"rendered":"

As discussed above, advanced renal hypoxia is observed in animal and human CKD. Despite
\n several controversies, HIF accumulation has been shown to occur at certain stages
\n during CKD, which is expected to protect against hypoxia 55<\/a>]\u201357<\/a>]. Nevertheless, in many CKD patients, kidney hypoxia does not improve and is rather
\n aggravated, and renal function shows a sustained decline, resulting in ESKD. To date,
\n several possible mechanisms have been proposed, which are discussed below (Fig.\u00a02<\/a>).<\/p>\n

\"thumbnail\"Fig. 2.<\/strong><\/a> Maladaptation to hypoxia during CKD progression. HIF accumulation occurring at certain
\n stages during CKD is expected to protect the kidney against hypoxia (blue squares on the left<\/em>). Nevertheless, in many CKD patients, kidney hypoxia does not improve, resulting
\n in ESKD via several mechanisms (red squares on the right<\/em>). Further details are explained in the text. HIF<\/em> hypoxia-inducible factor, DM<\/em> diabetes mellitus, VEGF<\/em> vascular endothelial growth factor, EPC<\/em> endothelial progenitor cell, UCP2<\/em> uncoupling protein 2\n <\/p>\n

Sustained capillary rarefaction<\/h4>\n

Capillary rarefaction in the kidney is a common feature that is intricately linked
\n to hypoxia in CKD 58<\/a>]. In human kidney biopsy samples, capillary densities are significantly associated
\n with renal function. Although HIF likely upregulates angiogenic factors, such as VEGF,
\n that theoretically leads to the restoration of capillary densities, this adaptation
\n mechanism usually fails; thus, capillary rarefaction is sustained and progressive.
\n Several possibilities have been suggested to explain the failure of capillary restoration
\n 59<\/a>]. First, VEGF expression in the kidney is decreased in CKD, which may indicate that
\n damaged tubular epithelial cells do not produce sufficient VEGF 60<\/a>]. The inflammatory environment, which is intricately linked to CKD, may also suppress
\n VEGF expression 61<\/a>]. Second, antiangiogenic factors (e.g., thrombospondin 1 and endostatin) have been
\n reported to be upregulated in several kidney diseases 61<\/a>]\u201363<\/a>]. Third, the incompetence of endothelial progenitor cells potentially underlies insufficient
\n capillary restoration 64<\/a>], although recent studies have questioned the direct involvement of bone marrow-derived
\n or circulating progenitor\/stem cells in blood vessel regeneration 65<\/a>], 66<\/a>].\n <\/p>\n

Increased oxygen consumption in tubules<\/h4>\n

Various factors are suggested to increase oxygen consumption in damaged tubules. Welch
\n et al. 67<\/a>], 68<\/a>] demonstrated increased oxygen consumption and decreased oxygen levels in the kidneys
\n of angiotensin II-infused or spontaneously hypertensive rats. These changes are probably
\n because of oxidative stress induced by angiotensin II, based on the restoration of
\n normal oxygen metabolism by the administration of tempol or an angiotensin II receptor
\n blocker. Indoxyl sulfate, a representative uremic toxin, may also be involved in increased
\n oxygen consumption in uremic kidneys via enhanced oxidative stress 69<\/a>]. Moreover, in diabetic kidney disease, upregulated mitochondrial uncoupling protein-2
\n is suggested to increase oxygen consumption in exchange of reducing oxidative stress
\n 70<\/a>], 71<\/a>].\n <\/p>\n

Impaired HIF activation<\/h4>\n

Activation of HIF in the kidney may be suboptimal in CKD despite profound renal hypoxia.
\n This concept is best exemplified in diabetic kidneys 72<\/a>], 73<\/a>] but may apply in CKD of nondiabetic etiologies.\n <\/p>\n

A large body of evidence suggests that cellular adaptation to hypoxia is impaired
\n in the diabetic milieu and that deregulated HIF-1? may be a significant contributor
\n 74<\/a>], 75<\/a>]. Methylglyoxal, a highly reactive dicarbonyl metabolite that is increased in diabetes,
\n has been shown to be a key player in the impairment of the HIF-1 pathway. Methylglyoxal
\n modifies specific arginine residues in HIF-1? and blocks heterodimer formation with
\n HIF-1? 76<\/a>]. The interaction between HIF-1? and p300 is also inhibited by methylglyoxal via modification
\n of an asparagine residue at p300 77<\/a>]. In addition to the functional suppression of HIF-1, methylglyoxal may inhibit HIF-1
\n activity via enhanced degradation. Bento et al. 29<\/a>] demonstrated that methylglyoxal increased association of HIF-1? with HSP40 and HSP70,
\n leading to CHIP recruitment and polyubiquitination of HIF-1?. This may be because
\n of the increased levels of modified and monomeric HIF-1? resulting from the inhibited
\n association of HIF-1? with HIF-1? and p300.\n <\/p>\n

Additional mechanisms of the suppression of HIF activation in advanced CKD, including
\n nondiabetic etiologies, have been proposed. We previously reported that at clinically
\n relevant concentrations, indoxyl sulfate upregulated CBP\/p300-interacting transactivator
\n with Glu\/Asp-rich carboxy-terminal domain 2 (CITED2) via post-transcriptional mRNA
\n stabilization, which in turn inhibited the interaction between p300 and HIF-1? C-terminal
\n transactivation domain, resulting in suppressed HIF-1 transactivation activity 78<\/a>]. Deficient HIF-1 transcriptional activity may also be caused by a decrease in the
\n expression of p300\/CBP-associated factor, which is observed in adipose tissue-derived
\n mesenchymal stem cells of dialysis patients as compared with those of nondialysis
\n patients 79<\/a>].\n <\/p>\n","protected":false},"excerpt":{"rendered":"

As discussed above, advanced renal hypoxia is observed in animal and human CKD. Despite several controversies, HIF accumulation has been shown to occur at certain stages during CKD, which is expected to protect against hypoxia 55]\u201357]. Nevertheless, in many CKD patients, kidney hypoxia does not improve and is rather aggravated, and renal function shows a Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-90880","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/90880","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/comments?post=90880"}],"version-history":[{"count":0,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/90880\/revisions"}],"wp:attachment":[{"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/media?parent=90880"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/categories?post=90880"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/tags?post=90880"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}