Editors' ChoicePhysiology

Channel Repression in Diabetic Kidneys

Sci. Signal.  14 May 2013:
Vol. 6, Issue 275, pp. ec106
DOI: 10.1126/scisignal.2004321

Diabetes-related kidney disease is associated with aberrant function of the mesangial cells (MCs), which regulate kidney blood flow, caused by oxidative stress induced by chronic exposure to high concentrations of glucose. Prolonged exposure to reactive oxygen species (ROS) activates PKC (protein kinase C) and decreases the abundance of TRPC6 (transient receptor potential cation channel, subfamily C, member 6), a calcium channel that promotes the contractile function of MCs. Wang et al. found that ROS induced repressive chromatin remodeling of the TRPC6 promoter that involved both PKC and the transcription factor NF-κB (nuclear factor κB). Treatment of human MCs with H2O2 or phorbitol 12-myristate 13-acetate (PMA), a PKC activator, induced a time-dependent decrease in the abundance of TRPC6 mRNA and protein. Silencing the NF-κB inhibitor IκBα also reduced TRPC6 abundance and prevented Ca2+ influx by the TRPC6 activator hyperforin. NF-κB inhibitors prevented the H2O2- or PMA-induced decrease in TRPC6 abundance, as well as increasing both basal and hyperforin-induced Ca2+ influx. PMA induced the phosphorylation of IκBα and thereby stimulated the nuclear translocation and DNA binding activity of NF-κB. Knocking down the p65, but not the p50, subunit of NF-κB prevented the H2O2-induced decrease in TRPC6 abundance and increased its basal abundance, suggesting a role for p65 in maintaining TRPC6 homeostasis. PMA induced the binding of p65 to the TRPC6 promoter and its association with HDAC2 (histone deacetylase 2) in human MCs, which decreased the acetylation of histone H3 in the promoter. Knockdown of HDAC2 or treatment with the HDAC inhibitor trichostatin A prevented the H2O2-induced decrease in TRPC6 abundance. Thus, by stimulating epigenetic repression of TRPC6, chronically increased glucose may compromise blood flow in the kidney, contributing to loss of kidney function.

Y. Wang, M. Ding, S. Chaudhari, Y. Ding, J. Yuan, D. Stankowska, S. He, R. Krishnamoorthy, J. T. Cunningham, R. Ma, Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells. J. Biol. Chem. 288, 12852–12865 (2013) [Abstract] [Full Text]