Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress

Abstract

Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.

Live Imaging of Calciprotein Particle Clearance and Receptor Mediated Uptake: Role of Calciprotein Monomers

“…We conclude that CPM are taken up earlier and at a higher rate and therefor are better visible even without leupeptin treatment. This is in full agreement with results described in Matsui et al (2013) , Mizuno et al (1991) and Rudloff et al (2021) that intriguingly show increased fetuin-A staining intensity in proximal tubule lumen if re-uptake is inhibited by His-Rap megalin ( Matsui et al, 2013 ) or by Clcn5 knockout ( Ewence et al, 2008 ), or is increased in proximal tubule epithelial cells, if lysosomal degradation is inhibited by leupeptin ( Matsui et al, 2013 ). Nevertheless, small amounts of free fetuin-A, like albumin [around 3 μg/ml in proximal tubular fluid in rats ( Leber and Marsh, 1970 )], may pass the renal filtration barrier, and will also be re-absorbed by proximal tubule epithelial cells.…”

“…Another major finding was, that all cell types associated with CPM or CPP clearance (macrophages, LSEC, kidney epithelial cells) endocytosed both CPM and CPP when directly exposed in cell cultures. However, in vivo CPP injection experiments never detected CPP in kidneys, hence proximal tubule epithelial cells in vivo will never contact CPP unless they are formed in situ , which has in fact been observed in kidney damage models ( Rudloff et al, 2021 ). In contrast LSEC, or endothelial cells in general, and macrophages are certainly among the first cells contacting CPM and CPP.…”

Dichotomous Responses to Chronic Fetal Hypoxia Lead to a Predetermined Aging Phenotype

“…1 A ), a hypoxic chamber was used. Similar to our previous work ( 27 ), dams quickly adapted to the hypoxic environment, and at birth litter size and placental mass were similar to normoxic control gestations ( supplemental Fig. S1 , A – C ).…”

Fetuin-A and risk of diabetes-related vascular complications: a prospective study

“…The positive association between fetuin-A and insulin resistance is supported by epidemiologic studies [ 2 , 36 ] and in mice, injection of recombinant fetuin-A decreases insulin sensitivity, Ahsg −/− mice are insulin-sensitive and resistant to weight gain when fed a high-fat diet [ 37 ]. On the other hand, fetuin-A is essential for the inhibition of the pro-inflammatory cytokine tumor necrosis factor and the NLRP3 inflammasome in macrophages, TGF-β1 antagonization and regulation of macrophage polarization [ 7 , 38 ]. We did not observe any statistically significant relationship between the inflammatory marker CRP or adiposity measures and fetuin-A, which is in line with previously published data from EPIC-Potsdam [ 15 ].…”