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-1 on renal epithelial permeability and directed sodium transport. This study was motivated by histological analysis of cystic kidneys showing increased expression levels of HIF-1 and HIF-2 We hypothesize that compression induced localized ischemia-hypoxia of normal epithelia near a cyst leads to local stabilization of HIF-1, leading to altered transepithelial transport that encourages cyst expansion. We found that stabilized HIF-1 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 mol/L Cobalt chloride (CoCl) was used acutely to stabilize HIF-1 in confluent cultures of mouse renal epithelia. We measured increased transepithelial permeability and decreased transepithelial resistance (TER) when HIF-1 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.