Hypoxia Inducible Factor 1-Alpha (HIF-1 Alpha) Is Induced during Reperfusion after Renal Ischemia and Is Critical for Proximal Tubule Cell Survival

Abstract

Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant.

MicroRNA-489 Induction by Hypoxia–Inducible Factor–1 Protects against Ischemic Kidney Injury

“…HIF-1 is known to be activated in ischemic AKI and has been reported to play a regulatory role in the underlying pathogenesis. 32,38,39 However, it remains unclear as to which HIF-1-regulated genes are critical to the regulation. In addition to the classic genes that facilitate oxygen delivery, angiogenesis, and anaerobic metabolism or glycolysis, 31,33 recent studies have documented HIF-1 regulation of miRs, such as miR-210, miR-21, miR-29, and miR-127.…”

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[240][241][242] Induction of AKI in animals by ischemia, radiocontrast agents, cisplatin, or rhabdomyolysis all induce oxygen tensions below 10 mm Hg deep within kidney tissue. 95,[243][244][245][246][247] In addition, impaired renal oxygenation has also been observed in human AKI. 248 Importantly, renal hypoxia is found not only during the acute phase of AKI but also up to 5 weeks later, after the recovery phase.…”

“…248 Importantly, renal hypoxia is found not only during the acute phase of AKI but also up to 5 weeks later, after the recovery phase. 243,249,250 This sustained hypoxia results in the kidney down-regulating pro-angiogenic isoform 164 and up-regulating dys-angiogenic isoforms 120 and 188 of vascular endothelial growth factor A (VEGF-A). 251,252 As a consequence, the vascular architecture of the kidney fails to be maintained with reductions in capillary number as well as individual capillary caliber and area.…”

The Role of Hypoxia-Inducible Factors in Organ Donation and Transplantation: The Current Perspective and Future Opportunities

“…Conde et al (19) have investigated both in the in vitro and in vivo settings the effect of stabilizing HIF-1a on the outcomes of IRI models. They exposed a proximal tubular HK-2 cell line to a period of 6 h of hypoxia and nutrient deprivation to mimic ischemia followed by re-oxygenation in a complete medium as an analogue of reperfusion (19).…”