Stabilization of hypoxia inducible factor by cobalt chloride can alter renal epithelial transport

Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we examined the effect of stabilized HIF-1α on renal epithelial permeability and directed sodium transport. This study was motivated by histological analysis of cystic kidneys showing increased expression levels of HIF-1α and HIF-2α. We hypothesize that compression induced localized ischemia-hypoxia of normal epithelia near a cyst leads to local stabilization of HIF-1α, leading to altered transepithelial transport that encourages cyst expansion. We found that stabilized HIF-1α alters both transcellular and paracellular transport through renal epithelial monolayers in a manner consistent with secretory behavior, indicating localized ischemia-hypoxia may lead to altered salt and water transport through kidney epithelial monolayers. A quantity of 100 µmol/L Cobalt chloride (CoCl2) was used acutely to stabilize HIF-1α in confluent cultures of mouse renal epithelia. We measured increased transepithelial permeability and decreased transepithelial resistance (TER) when HIF-1α was stabilized. Most interestingly, we measured a change in the direction of sodium current, most likely corresponding to abnormal secretory function, supporting our positive-feedback hypothesis.