Calcineurin β Regulates NADPH oxidases in Kidney Hypertrophy

Abstract

Renal failure occurs when kidneys are unable to appropriately adapt to stress. Hypertrophy, an adaptive response, enables an organ to meet functional demands. We reported that calcineurin (Cn) is required for kidney hypertrophy. Since studies have also implicated NADPH oxidases (Nox) in kidney changes, we hypothesize that Nox and Cn cooperate in a common signaling pathway. We tested this hypothesis in vitro using primary kidney cells lacking a catalytic subunit of Cn (CnAα−/− or CnAβ−/) and in vivo using WT and CnAβ−/− mice. In vitro, hypertrophic factors stimulate Cn activity in WT and CnAα−/− cells but fail to induce activity in CnAβ−/− cells. Furthermore, CnAβ over‐expression induces hypertrophy in WT cells; while, CnAβ−/− cells fail to develop hypertrophy, indicating that CnAβ is required for hypertrophy. Interestingly, CnAβ−/− cells generate less oxidative stress, suggesting that CnAβ‐mediated hypertrophy may involve Nox. Loss of CnAβ reduces expression of oxidative stress‐generating enzymes Nox2 and Nox4. Inhibition of NFAT, a CnAβ‐regulated transcription factor, decreases Nox2 and Nox4 expression, suggesting that the CnAβ‐NFAT pathway modulates Nox. In vivo, diabetic CnAβ−/− mice have diminished renal hypertrophy and less upregulation of Nox4. These data reveal that CnAβ‐NFAT regulates Nox expression and plays an important role in hypertrophy.