Abstract
The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized that the short-term adaptation to hypoxia is mediated via AMP-activated protein kinase (AMPK) and that it is coupled to the long-term adaptation by a common regulation mechanism, the HIF-hydroxylase enzymes. Further, we hypothesized the transepithelial transport of glucose to be part of this short-term adaptation. We conducted Ussing chamber studies using isolated lagomorph jejunum epithelium and cell culture experiments with CaCo-2 cells. The epithelia and cells were incubated under 100% and 21% O2, respectively, with the panhydroxylase inhibitor dimethyloxalylglycine (DMOG) or under 1% O2. We showed an activation of AMPK under hypoxia and after incubation with DMOG by Western blot. This could be related to functional effects like an impairment of Na+-coupled glucose transport. Inhibitor studies revealed a recruitment of glucose transporter 1 under hypoxia, but not after incubation with DMOG. Summing up, we showed an influence of hydroxylase enzymes on AMPK activity and similarities between hypoxia and the effects of hydroxylase inhibition on functional changes.
Highlights
Hypoxia is defined as “a state of cellular oxygen deprivation whereby the O2 requirements of a cell exceed that of available O2” [1]
While hypoxia-inducible factor (HIF) is considered to be the ‘master regulator’ of adaptation to hypoxia [4], its main mode of action is on the transcriptional level and, it takes some time for the adaptation reaction to be effective
We found a significant decrease of ∆m under hypoxia compared to control conditions (p < 0.05) and after preincubation with DMOG compared to the respective group of gassed epithelia incubated without DMOG (p < 0.05)
Summary
Hypoxia is defined as “a state of cellular oxygen deprivation whereby the O2 requirements of a cell exceed that of available O2” [1]. It has been shown that the activity of the sodium-coupled glucose transporter SGLT1 was diminished under hypoxia in jejunum epithelium [5,8,9] This downregulation appears to be a targeted and reasoned adaptation rather than a sign of cellular failure. PHDs are the central sensors of cellular oxygen supply and control the adaptation to hypoxia by mediating an oxygen-dependent hydroxylation of the cytoplasmic α subunit of HIF [22]. This oxygen-induced hydroxylation leads to the degradation of HIFα. 4 of 19 4 of 19 under hygproouxpias.o(nb)lyshaonwds wthiatthΔDmMwOasGdoecnrleyas(eudnbdye‘rh1y0p0ox%iaO’ (2grgeyasbsainrsg) )c.oTmhpiasreinddtoictahteescotnhtarot lingrhoiubpition of the PHDsgamssiemd iwcsitthh1e0e0%ffeocxtyogfenhy(wpohixteiaboanrs)thanedacatlsivoibtyy porfeSinGcuLbTa1t.ioTnhweitlharDgMerOdGec(hreaatcsheedofb∆arms). bByarDs MOG incubatiornepurensednetrmheyapno±xSiDa;(o3n9e-±w2ay rμeEpeqatcemd −m2eahs−u1remmienn−ts1)AcNoOmVpAawreidthtaoshubyspeoquxeiantaHloonlme–(S1i9d0ak±te1s7t 2 μEq cm−2 h−1bmaseind−o1n) Nhi=nt6s(aantiamsatlsr)o(nng=er10o(repaidthdeiltiiav))e, peff< e0c.0t5o, fdiDffMereOntGlecttoemrs pinadriecdatetosihgnyipfiocaxnitad. ifferences between groups
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