Renal hypoxia occurs in AKI of various etiologies, but adaptation to hypoxia, mediated by hypoxiainducible factor (HIF), is incomplete in these conditions. Preconditional HIF activation protects against renal ischemia-reperfusion injury, yet the mechanisms involved are largely unknown, and HIF-mediated renoprotection has not been examined in other causes of AKI. Here, we show that selective activation of HIF in renal tubules, through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO), protects from rhabdomyolysis-induced AKI. In this model, HIF activation correlated inversely with tubular injury. Specifically, VHL deletion attenuated the increased levels of serum creatinine/urea, caspase-3 protein, and tubular necrosis induced by rhabdomyolysis in wild-type mice. Moreover, HIF activation in nephron segments at risk for injury occurred only in VHL-KO animals. At day 1 after rhabdomyolysis, when tubular injury may be reversible, the HIF-mediated renoprotection in VHL-KO mice was associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal, as demonstrated by quantitative PCR, pathway enrichment analysis, and immunohistochemistry. In conclusion, a HIF-mediated shift toward improved energy supply may protect against acute tubular injury in various forms of AKI. 24: 180624: -181924: , 201324: . doi: 10.1681 No specific therapy is currently available for human AKI, a clinical entity of increasing incidence and high morbidity and mortality. 1-4 Rhabdomyolysis, one of the leading causes of AKI, develops after trauma, drug toxicity, infections, burns, and physical exertion. [5][6][7][8] The animal model using an intramuscular glycerol injection with consequent myoglobinuria is closely related to the human syndrome of rhabdomyolysis. 9 Experimental data demonstrate renal vasoconstriction, 9-15 tubular hypoxia, 15,16 normal or even reduced intratubular pressure, 9-11 as well as large variation in single nephron GFR. 10,11 Intratubular myoglobin casts, a histologic hallmark, seem not to cause tubular obstruction, 9-11 but rather scavenge nitric oxide 17,18 and generate reactive oxygen species 19 followed by vasoconstriction. J Am Soc NephrolThe traditional discrimination between ischemic and toxic forms of AKI has been challenged because an increasing amount of evidence suggests that renal hypoxia is a common denominator in AKI of different etiologies. 20 Pimonidazole adducts, which accumulate in tissues at oxygen tensions ,10 mmHg, 21 have been demonstrated in various AKI forms. 16,[22][23][24] During AKI, hypoxia-inducible factors (HIFs), which are mainly regulated by oxygen-dependent proteolysis, were found to be upregulated in different renal tubular segments. 16,20,22,24,25 HIFs are heterodimers of a constitutive b subunit, HIF-b (ARNT), and one of three oxygen-dependent a-subunits, HIF-1a, HIF-2a, and HIF-3a. The a-b dimers bind to hypoxia-response elements (HREs) in the promoter-enhancer region of HIF target genes. [26][27]...
The regulation of progenitor cell differentiation to a specific tissue type is one of the fundamental questions of biology. Here, we identify Osr1 and Osr2, 2 closely related genes encoding zinc finger transcription factors, as being strongly expressed in irregular connective tissue (ICT) fibroblasts in the chicken embryo, suitable as a developmental marker. We provide evidence that both Osr1 and Osr2 regulate mesenchymal cell-type differentiation. Both Osr1 and Osr2 can promote the formation of ICT, a cell type of so far unknown molecular specification, while suppressing differentiation of other tissues such as cartilage and tendon from uncommitted progenitors. Conversely, knockdown of either Osr gene alone or in combination reverses this effect, thereby leading to decreased differentiation of ICT fibroblasts and increased chondrogenesis in vitro. This indicates that Osr genes play a pivotal role in ICT fibroblast differentiation. Undifferentiated mesenchymal cells reside in the adult body in the form of mesenchymal stem cells in the bone marrow cavity. Using bone marrow stromal cells (BMSCs) isolated from chicken fetal long bones, we show that Osr1 and Osr2 have an intrinsic role in BMSC differentiation similar to their role in early embryonic development, that is, the enforcement of CT fibroblast differentiation and the repression of other cell types as exemplified here by osteoblast differentiation.
Animal genomes possess highly conserved cis-regulatory sequences that are often found near genes that regulate transcription and development. Researchers have proposed that the strong conservation of these sequences may affect the evolution of the surrounding genome, both by repressing rearrangement, and possibly by promoting duplicate gene retention. Conflicting data, however, have made the validity of these propositions unclear. Here, we use a new computational method to identify phylogenetically conserved noncoding elements (PCNEs) in a manner that is not biased by rearrangement and duplication. This method is powerful enough to identify more than a thousand PCNEs that have been conserved between vertebrates and the basal chordate amphioxus. We test 42 of our PCNEs in transgenic zebrafish assays-including examples from vertebrates and amphioxus-and find that the majority are functional enhancers. We find that PCNEs are enriched around genes with ancient synteny conservation, and that this association is strongest for extragenic PCNEs, suggesting that cis-regulatory interdigitation plays a key role in repressing genome rearrangement. Next, we classify mouse and zebrafish genes according to association with PCNEs, synteny conservation, duplication history, and presence in bidirectional promoter pairs, and use these data to cluster gene functions into a series of distinct evolutionary patterns. These results demonstrate that subfunctionalization of conserved cis-regulation has not been the primary determinate of gene duplicate retention in vertebrates. Instead, the data support the gene balance hypothesis, which proposes that duplicate retention has been driven by selection against dosage imbalances in genes with many protein connections.
Urothelial malignancies are associated with highly increased concentrations of calprotecin in the urine. In absence of renal failure and pyuria, calprotectin constitutes a promising biomarker for the detection of bladder cancer.
Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl-KO worsens the outcome of chronic CsA-induced renal toxicity.
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