Chronic hypoxia in cultured human podocytes inhibits BKCa channels by upregulating its β4-subunit.

Accumulating evidence suggests that podocyte hypoxia is an alternative mechanism for the pathogenesis of renal diseases. Functional, large-conductance, calcium-activated potassium channels (BK(Ca) channels) are expressed in podocytes as mechanosensitive channels; however, whether BK(Ca) channels are involved in the podocyte response to chronic hypoxia and the possible underlying mechanisms remain unclear. Here, we use the patch clamp technique to show that the exposure of human podocytes to 2% O(2) for 24 h causes a significant reduction in BK(Ca) channel currents. Molecular biology experiments showed that chronic hypoxia increased BK(Ca) channel β4-subunit mRNA and protein expression, but not the expression of the BK(Ca) pore-forming α- or β3-subunits. Furthermore, chronic hypoxia shifted the channel activation range toward more depolarized voltages and slowed its activation kinetics, which are similar to the properties conferred by the β4-subunit. We conclude that BK(Ca) channels are involved in the response of podocytes to chronic hypoxia via the upregulation of the β4-subunit. These findings provide new insight into the mechanism underlying the cellular responses of podocytes to hypoxia.