Kidney injury is independent of endothelial HIF-1α

Kalucka, Joanna; Schley, Gunnar; Georgescu, Adela; Klanke, Bernd; Rössler, Susanne; Baumgartl, J.; Velden, Joachim; Amann, Kerstin; Willam, Carsten; Johnson, Randall S.; Eckardt, Kai‐Uwe; Weidemann, Alexander

doi:10.1007/s00109-015-1264-4

Cited by 20 publications

(12 citation statements)

References 43 publications

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“…We and others have previously identified endothelial HIF-2 as the key transcription factor regulating postischemic kidney injury under PHD2-competent conditions, 14,44 whereas endothelial HIF-1 was dispensable. 14,45 Although these observations appear to contrast with this study, we believe that these are not conflicting findings. Our findings reveal that endothelial PHD2 deficiency reverses the susceptibility to AKI due to endothelial HIF-2 loss, 14 a response that involves endothelial HIF-1 signaling derived from an extrarenal vascular bed.…”

Section: Cre-ec-phd2 Hif2contrasting

confidence: 95%

Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

Rajendran

Schonfeld

Tiwari

et al. 2020

JASN

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BackgroundProlyl-4-hydroxylase domain-containing proteins 1–3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.MethodsTo investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.ResultsEndothelial deletion of Phd2 preserved kidney function and limited transition to CKD. Mechanistically, we found that endothelial Phd2 ablation protected against renal ischemia-reperfusion injury by suppressing the expression of proinflammatory genes and recruitment of inflammatory cells in a manner that was dependent on HIF-1 but not HIF-2. Persistence of renoprotective responses after acute inducible endothelial-specific loss of Phd2 in adult mice ruled out a requirement for PHD2 signaling in hematopoietic cells. Although Phd2 inhibition was not sufficient to induce detectable HIF activity in the kidney endothelium, in vitro experiments implicated a humoral factor in the anti-inflammatory effects generated by endothelial PHD2/HIF-1 signaling.ConclusionsOur findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.

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Section: Cre-ec-phd2 Hif2contrasting

confidence: 95%

Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

Rajendran

Schonfeld

Tiwari

et al. 2020

JASN

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“…Kalucka et al have observed that HIF‐1α does not affect renal development, renal vascular architecture, or renal function in endothelial cells and therefore is not related to CKD both in vivo (mice) and in vitro (endothelial cells). The only relationship of HIF‐1α in endothelial cells is to the survival in hypoxia and leukocyte adhesion, without any real link to the development of renal diseases.…”

Section: Discussionsupporting

confidence: 89%

“…Another revealed factor was that NF‐κB contributes to the activation of Ang 2 and that the combination of HIF‐1α and NF‐κB function as an advanced signalling cycle, persisting in raising the levels of both genes; this leads to the progression of hypertension, a number of endothelial vasoactive factors, and, consequently, CKD aggravating towards ESRD. In contrast to all the studies performed, Flisinski et al and Kalucka et al observed that HIF‐1α does not affect renal development.…”

Section: Discussionmentioning

confidence: 99%

Role of hypoxia‐inducible factor 1α as a potential biomarker for renal diseases—A systematic review

Encinas

Foncesca

Perez

et al. 2019

Cell Biochemistry & Function

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Renal cells need oxygen for homeostasis; it is known for adjusting cellular functioning and the energy obtainment have a broad relationship with cellular respiration, through the O2 bioavailability. O2 homeostasis regulation in the kidney is mediated by hypoxia‐inducible factors (HIFs). HIF is divided into three α isoforms, represented by HIF‐1α, HIF‐2α, and HIF‐3α in addition to three paralogs of HIF‐1β; these are involved in some metabolic processes, as well as in the pathogenesis of several diseases. Renal biopsy analyses of patients and experimental animal models aim to understand the relationship between HIF and protection against developing renal diseases or the induction of their onset, being thus this molecule can be considered a potential biomarker of renal disease. We carried out a systematic review to which we included studies on HIF‐1α and renal disease in the last 5 years (2013‐2018) in researches with humans and/or animal model through searches in three databases: LILACS, PubMed, and SciELO by two researchers. We obtained 22 articles that discussed the relationship with HIF as inductor or protector against renal disease and no relation between HIF and renal. We observed controversies remain regarding the relation between of HIF with renal diseases; this may be related to the different intracellular pathways mediated by HIF‐1α, thereby determining differentiated cellular responses.

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“…For example, Kalucka J et al found that loss of HIF-1α in glomerular endothelial cells increases hypoxic cell death in vitro, but in vivo, HIF-1α expression in endothelial cells in mouse kidneys is detectable but limited. As a result, endothelial cell-specific ablation of HIF-1α does not have obvious effects on developmental phenotype in the kidney and also no influence of renal function and adhesion molecules expression during fibrosis development after UUO [ 49 , 53 ]. Kapitsinou P et al further showed that inhibition of total endothelial HIF can aggravate renal fibrosis significantly in both ischemia-reperfusion and ureteral obstruction models.…”

Section: Hif In Chronic Kidney Disease (Ckd)-associated Renal Fibrmentioning

confidence: 99%

“…However, in vivo work indicates that HIF-1α expression in endothelial cells in mouse kidneys is detectable but limited. Therefore, endothelial cell-specific ablation of HIF-1α has no effect on kidney development and no influence on renal function and adhesion molecules expression during inflammation after UUO [ 53 ]. The limited role of endothelial HIF-1 in inflammation is also confirmed in another study [ 49 ].…”

Section: Hif In Ckd-associated Syndromesmentioning

confidence: 99%

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

Liu¹,

Wei²,

Guo³

et al. 2017

IJMS

107

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The pathogenesis of chronic kidney disease (CKD) is complex and apparently multifactorial. Hypoxia or decrease in oxygen supply in kidney tissues has been implicated in CKD. Hypoxia inducible factors (HIF) are a small family of transcription factors that are mainly responsive to hypoxia and mediate hypoxic response. HIF plays a critical role in renal fibrosis during CKD through the modulation of gene transcription, crosstalk with multiple signaling pathways, epithelial-mesenchymal transition, and epigenetic regulation. Moreover, HIF also contributes to the development of various pathological conditions associated with CKD, such as anemia, inflammation, aberrant angiogenesis, and vascular calcification. Treatments targeting HIF and related signaling pathways for CKD therapy are being developed with promising clinical benefits, especially for anemia. This review presents an updated analysis of hypoxia response, HIF, and their associated signaling network involved in the pathogenesis of CKD.

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Kidney injury is independent of endothelial HIF-1α

Cited by 20 publications

References 43 publications

Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1

Role of hypoxia‐inducible factor 1α as a potential biomarker for renal diseases—A systematic review

Hypoxia, HIF, and Associated Signaling Networks in Chronic Kidney Disease

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