Calcineurin Aß regulates NADPH oxidase (Nox) expression and activity via nuclear factor of activated T cells (NFAT) in response to high glucose.
J Biol Chem
; 289(8): 4896-905, 2014 Feb 21.
Article
in En
| MEDLINE
| ID: mdl-24371139
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 Aß 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 CnAß(-/-)), we found that high glucose selectively activates CnAß, whereas CnAα is constitutively active. Furthermore, CnAß but not CnAα mediates hypertrophy. Next, we found that chronic reactive oxygen species generation in response to high glucose is attenuated in CnAß(-/-) cells, suggesting that Cn is upstream of Nox. Consistent with this, loss of CnAß reduces basal expression and blocks high glucose induction of Nox2 and Nox4. Inhibition of nuclear factor of activated T cells (NFAT), a CnAß-regulated transcription factor, decreases Nox2 and Nox4 expression, whereas NFAT overexpression increases Nox2 and Nox4, indicating that the CnAß/NFAT pathway modulates Nox. These data reveal that the CnAß/NFAT pathway regulates Nox and plays an important role in high glucose-mediated hypertrophic responses in the kidney.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Membrane Glycoproteins
/
NADPH Oxidases
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Calcineurin
/
NFATC Transcription Factors
/
Glucose
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Biol Chem
Year:
2014
Document type:
Article
Country of publication:
United States