Calcineurin A beta Regulates NADPH Oxidase ( Nox) Expression and Activity via Nuclear Factor of Activated T Cells ( NFAT) in Response to High Glucose*

• Type of Material: Article
• Authors: Clintoria Williams, Emory University; Jennifer Gooch, Emory University
• Language: English
• Date: 2014-02-21
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M113.514869
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 289
• Issue: 8
• Start Page: 4896
• End Page: 4905
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health, NIDDK, Grant T32 DK00756 (to C. R. W.).; This work was also supported by a Department of Veterans Affairs MERIT award (to J. L. G.).
• Keywords: RENAL INJURY; Calcineurin; NEPHROTOXICITY; Biochemistry & Molecular Biology; NAD(P)H OXIDASE; Reactive Oxygen Species (ROS); NFAT Transcription Factor; ACCUMULATION; Oxidative Stress; GROWTH-FACTOR-BETA; STREPTOZOTOCIN; Life Sciences & Biomedicine; Science & Technology; High Glucose; Renal Hypertrophy; NADPH Oxidase; FIBRONECTIN; Kidney; HYPERTROPHY; ALPHA; DIABETIC KIDNEY
• Research Categories: Chemistry, Biochemistry; Health Sciences, General

Abstract

Hypertrophy is an adaptive response that enables organs to appropriately meet increased functional demands. Previously, we reported that calcineurin (Cn) is required for glomerular and whole kidney hypertrophy in diabetic rodents (Gooch, J. L., Barnes, J. L., Garcia, S., and Abboud, H. E. (2003). Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation. Am. J. Physiol. Renal Physiol. 284, F144–F154; Reddy, R. N., Knotts, T. L., Roberts, B. R., Molkentin, J. D., Price, S. R., and Gooch, J. L. (2011). Calcineurin Aβ is required for hypertrophy but not matrix expansion in the diabetic kidney. J. Cell Mol. Med. 15, 414–422). Because studies have also implicated the reactive oxygen species-generating enzymes NADPH oxidases (Nox) in diabetic kidney responses, we tested the hypothesis that Nox and Cn cooperate in a common signaling pathway. First, we examined the role of the two main isoforms of Cn in hypertrophic signaling. Using primary kidney cells lacking a catalytic subunit of Cn (CnAα−/− or CnAβ−/−), we found that high glucose selectively activates CnAβ, whereas CnAα is constitutively active. Furthermore, CnAβ but not CnAα mediates hypertrophy. Next, we found that chronic reactive oxygen species generation in response to high glucose is attenuated in CnAβ−/− cells, suggesting that Cn is upstream of Nox. Consistent with this, loss of CnAβ reduces basal expression and blocks high glucose induction of Nox2 and Nox4. Inhibition of nuclear factor of activated T cells (NFAT), a CnAβ-regulated transcription factor, decreases Nox2 and Nox4 expression, whereas NFAT overexpression increases Nox2 and Nox4, indicating that the CnAβ/NFAT pathway modulates Nox. These data reveal that the CnAβ/NFAT pathway regulates Nox and plays an important role in high glucose-mediated hypertrophic responses in the kidney.