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]–57]. Nevertheless, in many CKD patients, kidney hypoxia does not improve and is rather
aggravated, and renal function shows a sustained decline, resulting in ESKD. To date,
several possible mechanisms have been proposed, which are discussed below (Fig. 2).
Fig. 2. Maladaptation to hypoxia during CKD progression. HIF accumulation occurring at certain
stages during CKD is expected to protect the kidney against hypoxia (blue squares on the left). Nevertheless, in many CKD patients, kidney hypoxia does not improve, resulting
in ESKD via several mechanisms (red squares on the right). Further details are explained in the text. HIF hypoxia-inducible factor, DM diabetes mellitus, VEGF vascular endothelial growth factor, EPC endothelial progenitor cell, UCP2 uncoupling protein 2
Sustained capillary rarefaction
Capillary rarefaction in the kidney is a common feature that is intricately linked
to hypoxia in CKD 58]. In human kidney biopsy samples, capillary densities are significantly associated
with renal function. Although HIF likely upregulates angiogenic factors, such as VEGF,
that theoretically leads to the restoration of capillary densities, this adaptation
mechanism usually fails; thus, capillary rarefaction is sustained and progressive.
Several possibilities have been suggested to explain the failure of capillary restoration
59]. First, VEGF expression in the kidney is decreased in CKD, which may indicate that
damaged tubular epithelial cells do not produce sufficient VEGF 60]. The inflammatory environment, which is intricately linked to CKD, may also suppress
VEGF expression 61]. Second, antiangiogenic factors (e.g., thrombospondin 1 and endostatin) have been
reported to be upregulated in several kidney diseases 61]–63]. Third, the incompetence of endothelial progenitor cells potentially underlies insufficient
capillary restoration 64], although recent studies have questioned the direct involvement of bone marrow-derived
or circulating progenitor/stem cells in blood vessel regeneration 65], 66].
Increased oxygen consumption in tubules
Various factors are suggested to increase oxygen consumption in damaged tubules. Welch
et al. 67], 68] demonstrated increased oxygen consumption and decreased oxygen levels in the kidneys
of angiotensin II-infused or spontaneously hypertensive rats. These changes are probably
because of oxidative stress induced by angiotensin II, based on the restoration of
normal oxygen metabolism by the administration of tempol or an angiotensin II receptor
blocker. Indoxyl sulfate, a representative uremic toxin, may also be involved in increased
oxygen consumption in uremic kidneys via enhanced oxidative stress 69]. Moreover, in diabetic kidney disease, upregulated mitochondrial uncoupling protein-2
is suggested to increase oxygen consumption in exchange of reducing oxidative stress
70], 71].
Impaired HIF activation
Activation of HIF in the kidney may be suboptimal in CKD despite profound renal hypoxia.
This concept is best exemplified in diabetic kidneys 72], 73] but may apply in CKD of nondiabetic etiologies.
A large body of evidence suggests that cellular adaptation to hypoxia is impaired
in the diabetic milieu and that deregulated HIF-1? may be a significant contributor
74], 75]. Methylglyoxal, a highly reactive dicarbonyl metabolite that is increased in diabetes,
has been shown to be a key player in the impairment of the HIF-1 pathway. Methylglyoxal
modifies specific arginine residues in HIF-1? and blocks heterodimer formation with
HIF-1? 76]. The interaction between HIF-1? and p300 is also inhibited by methylglyoxal via modification
of an asparagine residue at p300 77]. In addition to the functional suppression of HIF-1, methylglyoxal may inhibit HIF-1
activity via enhanced degradation. Bento et al. 29] demonstrated that methylglyoxal increased association of HIF-1? with HSP40 and HSP70,
leading to CHIP recruitment and polyubiquitination of HIF-1?. This may be because
of the increased levels of modified and monomeric HIF-1? resulting from the inhibited
association of HIF-1? with HIF-1? and p300.
Additional mechanisms of the suppression of HIF activation in advanced CKD, including
nondiabetic etiologies, have been proposed. We previously reported that at clinically
relevant concentrations, indoxyl sulfate upregulated CBP/p300-interacting transactivator
with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) via post-transcriptional mRNA
stabilization, which in turn inhibited the interaction between p300 and HIF-1? C-terminal
transactivation domain, resulting in suppressed HIF-1 transactivation activity 78]. Deficient HIF-1 transcriptional activity may also be caused by a decrease in the
expression of p300/CBP-associated factor, which is observed in adipose tissue-derived
mesenchymal stem cells of dialysis patients as compared with those of nondialysis
patients 79].