BACKGROUND: Hypoxia inducible factor 1 (HIF-1) activates protective pathways to counteract hypoxia and prevent tissue damage in conjunction with renal injury. The aim of this study was to evaluate a role of HIF-1 in diabetes-induced kidney damage. METHODS: We used a streptozotocin-induced diabetes mouse model and compared biochemical, histological and molecular parameters associated with kidney damage in Hif1α deficient (Hif1α +/- ) and wild-type mice. RESULTS: We showed that Hif1α deficiency accelerated pathological changes in the early stage of DN. Six weeks after diabetes-induction, Hif1α deficient mice showed more prominent changes in biochemical serum parameters associated with glomerular injury, increased expression of podocyte damage markers, and loss of podocytes compared to wild-type mice. These results indicate that Hif1α deficiency specifically affects podocyte survival in the early phase of DN, resulting in diabetic glomerular injury. In contrast, renal fibrosis was not affected by the global reduction of Hif1α, at least not in the early phase of diabetic exposure. CONCLUSIONS: Together our data reveal that HIF-1 has an essential role in the early response to prevent diabetes-induced tissue damage and that impaired HIF-1 signaling results in a faster progression of DN. Although the modulation of HIF-1 activity is a high-priority target for clinical treatments, further study is required to investigate HIF-1 as a potential therapeutic target for the treatment of DN.

• Klíčová slova
• Diabetic complications, Diabetic nephropathy, Hypoxia, Mouse model, Podocyte,
• MeSH
• diabetické nefropatie etiologie   metabolismus   patologie   MeSH
• experimentální diabetes mellitus komplikace   patofyziologie   MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa nedostatek   genetika   MeSH
• modely nemocí na zvířatech * MeSH
• myši MeSH
• prognóza MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč

Although physiological responses to chronic hypoxia, including pulmonary hypertension and right ventricular hypertrophy, have been well described, the molecular mechanisms involved in cardiopulmonary adaptations are still not fully understood. We hypothesize that adaptive responses to chronic hypoxia are the result of altered transcriptional regulations in the right and left ventricles. Here we report results from the gene expression profiling of adaptive responses in a chronically hypoxic heart. Of 11 analyzed candidate genes, the expression of seven and four genes, respectively, was significantly altered in the right ventricle of hypoxic male and female mice. In the transcriptional profile of the left ventricle, we identified a single expression change in hypoxic males (Vegfa gene). To directly test the role of HIF1, we analyzed the expression profile in Hif1a partially deficient mice exposed to moderate hypoxia. Our data showed that Hif1a partial deficiency significantly altered transcriptional profiles of analyzed genes in hypoxic hearts. The expression changes were only detected in two genes in the right ventricle of Hif1a(+/-) males and in one gene in the right ventricle of Hif1a(+/-) females. First, our results suggest that hypoxia mainly affects adaptive expression profiles in the right ventricle and that each ventricle can respond independently. Second, our findings indicate that HIF1a plays an important role in adaptive cardiopulmonary responses and the dysfunction of HIF1 pathways considerably affects transcriptional regulation in the heart. Third, our data reveal significant differences between males and females in cardiac adaptive responses to hypoxia and indicate the necessity of optimizing diagnostic and therapeutic procedures in clinical practice, with respect to sex.

• MeSH
• časové faktory MeSH
• chronická nemoc MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa nedostatek   genetika   metabolismus   MeSH
• fyziologická adaptace MeSH
• genetická transkripce MeSH
• hematokrit MeSH
• hypoxie genetika   metabolismus   patofyziologie   MeSH
• kardiomegalie genetika   metabolismus   patofyziologie   MeSH
• krevní tlak MeSH
• messenger RNA metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• plicní hypertenze genetika   metabolismus   patofyziologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulace genové exprese MeSH
• sexuální faktory MeSH
• srdce - funkce komor genetika   MeSH
• srdeční komory metabolismus   patofyziologie   MeSH
• stanovení celkové genové exprese * metody   MeSH
• tělesná hmotnost MeSH
• vaskulární endoteliální růstový faktor A genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• faktor 1 indukovatelný hypoxií - podjednotka alfa MeSH
• Hif1a protein, mouse MeSH Prohlížeč
• messenger RNA MeSH
• vascular endothelial growth factor A, mouse MeSH Prohlížeč
• vaskulární endoteliální růstový faktor A MeSH