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Hypoxia Inducible Factor 1: A Urinary Biomarker of Kidney Disease.

ABSTRACT: Identifying noninvasive biomarkers of kidney disease is valuable for diagnostic and therapeutic purposes. Hypoxia inducible factor 1 (HIF-1) expression is known to be elevated in the kidneys in several renal disease pathologies. We hypothesized that the urinary HIF-1a mRNA level may be a suitable biomarker for expression of this protein in chronic kidney disease (CKD). We compared HIF-1a mRNA levels from urine pellets of CKD and healthy subjects. To ensure that urinary HIF-1a mRNA is of kidney origin, we examined colocalization of HIF-1a mRNA with two kidney specific markers in urine cells. We found that HIF-1a mRNA is readily quantifiable in urine pellets and its expression was significantly higher in CKD patients compared with healthy adults. We also showed that the urinary HIF-1a mRNA comes primarily from cells of renal origin. Our data suggest that urinary HIF-1a mRNA is a potential biomarker in CKD and can be noninvasively assessed in patients.

SUBMITTER: Movafagh S

PROVIDER: S-EPMC5421733 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Hypoxia Inducible Factor 1: A Urinary Biomarker of Kidney Disease.

Movafagh S S Raj D D Sanaei-Ardekani M M Bhatia D D Vo K K Mahmoudieh M M Rahman R R Kim E H EH Harralson A F AF

Clinical and translational science 20170209 3

Identifying noninvasive biomarkers of kidney disease is valuable for diagnostic and therapeutic purposes. Hypoxia inducible factor 1 (HIF-1) expression is known to be elevated in the kidneys in several renal disease pathologies. We hypothesized that the urinary HIF-1a mRNA level may be a suitable biomarker for expression of this protein in chronic kidney disease (CKD). We compared HIF-1a mRNA levels from urine pellets of CKD and healthy subjects. To ensure that urinary HIF-1a mRNA is of kidney o ...[more]

PMID: 28181420

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Project description: Not available

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Project description:In polycystic kidney disease (PKD), erythropoietin (EPO) production and interstitial vascularization are increased compared with other kidney diseases. EPO and several angiogenic factors are controlled by hypoxia-inducible transcription factors (HIFs), which are composed of a constitutive beta-subunit and two alternative alpha-subunits (HIF-1alpha, HIF-2alpha). We hypothesized that cyst expansion may result in pericystic hypoxia and consecutive up-regulation of HIF and thus examined the expression of HIF-alpha and HIF target genes in human PKD and in a rodent PKD model. HIF-1alpha and HIF-2alpha were found to be up-regulated in cyst epithelium and cells of cyst walls, respectively. The distinct expression pattern of the HIF-alpha isoforms closely resembles the respective pattern in normal kidneys under systemic hypoxia. Pimonidazole staining, a marker for tissue hypoxia, confirmed the existence of regional hypoxia in polycystic kidneys. Immunohistochemistry for selected target genes implicated a role for HIF-1alpha in vascular endothelial growth factor and Glut-1 activation and HIF-2alpha in endoglin and EPO stimulation. Polycystin-deficient cells showed physiological, oxygen-dependent HIF-alpha modulation, excluding a direct influence of polycystin deficiency on HIF-alpha regulation. In conclusion, HIF accumulation in human and rat PKD seems to be responsible for increased EPO production and pericystic hypervascularity and may have an impact on progression of PKD.

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| S-EPMC6025987 | biostudies-literature

Use of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, in chronic kidney disease-associated anemia in cats.

Project description:BackgroundErythropoietic effects of molidustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, were previously demonstrated in healthy cats.ObjectiveTo evaluate the safety and erythropoietic effects of daily PO administration of molidustat in anemic cats with chronic kidney disease (CKD).AnimalsTwenty-one client-owned CKD cats (4-17 years old) with anemia.MethodsMulticenter field study; randomized, masked, and placebo-controlled. Cats were treated PO once daily for 28 days with suspensions of control product (CP; n = 6) or 5 mg/kg of molidustat (n = 15). Hematocrit (HCT) was evaluated at weekly intervals. Individual cat treatment success was defined as a ≥4% point increase in HCT compared to baseline.ResultsControl group mean HCT remained low throughout the study (20.1%-23.4%). Mean HCT of molidustat-treated cats increased weekly, and a significant increase compared to baseline (23.6%) was first observed on Day 21 (27.3%; P < .001; 95% confidence interval [CI], 1.69-5.67). Compared to CP group, mean HCT was significantly higher on Day 21 (27.3% vs 20.1%; P < .001; 95% CI, 2.91-10.75) but not significantly higher on Day 28 (27.8% vs 23.4%; P = .06; 95% CI, -0.23 to 9.88). The number of individual treatment successes on Day 28 was higher among remaining molidustat-treated cats (7/14) compared to remaining control cats (1/5), but there was no significant difference between groups.Conclusions and clinical importanceDaily PO molidustat administration may stimulate a clinically relevant erythropoietic response in anemic cats with CKD. This HIF-PH inhibitor may be an alternative for managing anemia in cats compared to recombinant EPO treatment.

| S-EPMC10800191 | biostudies-literature

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