Kalucka Joanna, Schley Gunnar, Georgescu Adela, Klanke Bernd, Rössler Susanne, Baumgartl Jasmin, Velden Joachim, Amann Kerstin, Willam Carsten, Johnson Randall S, Eckardt Kai-Uwe, Weidemann Alexander
Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Ulmenweg 18, 91054, Erlangen, Germany.
J Mol Med (Berl). 2015 Aug;93(8):891-904. doi: 10.1007/s00109-015-1264-4. Epub 2015 Mar 11.
Hypoxia-inducible transcription factors (HIFs) control cellular adaptation to low oxygen. In the kidney, activation of HIF is beneficial during injury; however, the specific contribution of HIF-1α in renal endothelial cells (EC) remains elusive. Since EC display tissue-specific heterogeneity, we investigated how HIF-1α affects key functions of glomerular EC in vitro and its contribution to renal development and pathophysiological adaptation to acute or chronic renal injury in vivo. Loss of HIF-1α in glomerular EC induces hypoxic cell death and reduces hypoxic adhesion of macrophages in vitro. In vivo, HIF-1α expression in EC in mouse kidneys is detectable but limited. Accordingly, EC-specific ablation of HIF-1α does not lead to developmental or phenotypical abnormalities in the kidney. Renal function and expression of adhesion molecules during acute ischemic kidney injury is independent of HIF-1α in EC. Likewise, inflammation and development of fibrosis after unilateral ureteric obstruction is not influenced by endothelial HIF-1α. Taken together, although HIF-1α exerts effects on glomerular EC in vitro, endothelial HIF-1α does not influence renal development and pathophysiological adaptation to kidney injury in vivo. This implies a profound difference of the hypoxic response of the renal vascular bed compared to other organs, such as the heart. This has implications for the development of pharmacological strategies targeting the endothelial hypoxic response pathways.
HIF-1α controls hypoxic survival and adhesion on endothelial cells (EC) in vitro. In vivo, HIF-1α expression in renal EC is low. Deletion of HIF-1α in EC does not affect kidney development and function in mice. Renal function after acute and chronic kidney injury is independent of HIF-1α in EC. Data suggest organ-specific regulation of HIF-1α function in EC.
缺氧诱导转录因子（HIFs）控制细胞对低氧的适应性。在肾脏中，HIF的激活在损伤期间是有益的；然而，HIF-1α在肾内皮细胞（EC）中的具体作用仍不清楚。由于内皮细胞表现出组织特异性异质性，我们研究了HIF-1α如何在体外影响肾小球内皮细胞的关键功能，以及它在体内对肾脏发育和对急性或慢性肾损伤的病理生理适应性的贡献。肾小球内皮细胞中HIF-1α的缺失会诱导缺氧细胞死亡，并降低体外巨噬细胞的缺氧黏附。在体内，小鼠肾脏内皮细胞中可检测到HIF-1α的表达，但水平有限。因此，内皮细胞特异性敲除HIF-1α不会导致肾脏发育或表型异常。急性缺血性肾损伤期间的肾功能和黏附分子表达独立于内皮细胞中的HIF-1α。同样，单侧输尿管梗阻后的炎症和纤维化发展不受内皮HIF-1α的影响。综上所述，尽管HIF-1α在体外对肾小球内皮细胞有作用，但内皮HIF-1α在体内不影响肾脏发育和对肾损伤的病理生理适应性。这意味着肾血管床与其他器官（如心脏）的缺氧反应存在深刻差异。这对针对内皮缺氧反应途径的药理策略的开发具有重要意义。
HIF-1α在体外控制内皮细胞（EC）的缺氧存活和黏附。在体内，肾内皮细胞中HIF-1α的表达较低。内皮细胞中HIF-1α的缺失不影响小鼠的肾脏发育和功能。急性和慢性肾损伤后的肾功能独立于内皮细胞中的HIF-1α。数据表明内皮细胞中HIF-1α功能存在器官特异性调节。
