Calcineurin A-β is required for hypertrophy but not matrix expansion in the diabetic kidney.
Bottom Line: The absence of β produced a significant decrease in total calcineurin activity in the inner medulla (IM) and reduced nuclear factor of activated T-cells (NFATc) activity.In conclusion, loss of the β isoform of calcineurin is sufficient to reproduce beneficial aspects of cyclosporine on diabetic renal hypertrophy but not matrix expansion.Therefore, while multiple signals appear to regulate matrix, calcineurin β appears to be a central mechanism involved in organ hypertrophy.
Affiliation: Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.Show MeSH
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Mentions: After 6 weeks of diabetes, kidneys were harvested and total calcineurin activity and NFATc transactivation of a luciferase reporter were examined in renal cortices, OM and IM. First, the data show that calcineurin activity is generally similar in the cortex, OM, and IM of wild-type mice. Loss of the β isoform results in a significant decrease in the IM, consistent with previous reports that the IM is the site of highest β expression . In wild-type mice, induction of diabetes did not change calcineurin activity in any kidney section. Interestingly, there was a significant increase in total calcineurin activity in the IM of β−/− mice with STZ treatment, suggesting that the remaining α isoform is activated in response to diabetes (Fig. 2A). Next, Fig. 2B shows that NFATc-mediated luciferase activity was highest in the IM (plotted on the right axis) and lowest in the cortex of wild-type mice. Loss of calcineurin β led to a significant decrease in NFATc activity in the IM, consistent with decreased activity shown in Fig. 2A. In contrast to the absence of an effect on overall calcineurin activity, diabetes reduced activity of the NFATc reporter construct in the wild-type mice. NFATc activity was slightly reduced in the cortex and OM and significantly decreased in the IM. There was no difference, however, in NFATc activity in the IM of diabetic β−/− mice.
Affiliation: Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.