title: Compensatory renal hypertrophy following uninephrectomy is calcineurin-independent.
abstract: Calcineurin is a calcium-dependent phosphatase that is involved in many cellular processes including hypertrophy. Inhibition or genetic loss of calcineurin blocks pathological cardiac hypertrophy and diabetic renal hypertrophy. However, calcineurin does not appear to be involved in physiological cardiac hypertrophy induced by exercise. The role of calcineurin in a compensatory, non-pathological model of renal hypertrophy has not been tested. Therefore, in this study, we examined activation of calcineurin and the effect of calcineurin inhibition or knockout on compensatory hypertrophy following uninephrectomy (UNX). UNX induces ~15% increase in the size of the remaining kidney; the data show no change in the generation of reactive oxygen species (ROS), Nox4 or transforming growth factor-β expression confirming the model as one of compensatory hypertrophy. Next, analyses of the remaining kidney reveal that total calcineurin activity is increased, and, to a lesser extent, transcriptional activity of the calcineurin substrate nuclear factor of activated T cell is up-regulated following UNX. However, inhibition of calcineurin with cyclosporine failed to prevent compensatory renal hypertrophy. Likewise, hypertrophy was comparable to WT in mice lacking either isoform of the catalytic subunit of calcineurin (CnAα-/- or CnAβ-/-). In conclusion, similar to its role in the heart, calcineurin is required for pathological but not compensatory renal hypertrophy. This separation of signalling pathways could therefore help further define key factors necessary for pathological hypertrophy including diabetic nephropathy.
authors.affiliation: Atlanta Veterans Administration Medical Center, Decatur, GA, USA; Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Clintoria R
authors.initials: CR
authors.lastname: Williams
authors.forename: Brandi M
authors.initials: BM
authors.lastname: Wynne
authors.forename: Makeeva
authors.initials: M
authors.lastname: Walker
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hoover
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gooch
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006984:Hypertrophy / Q000209:etiology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D018345:Mice, Knockout; D009392:Nephrectomy / Q000009:adverse effects / Q000379:methods*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020033:Protein Isoforms; D019703:Calcineurin
keywords: NFAT; calcineurin; cyclosporin; renal hypertrophy; uninephrectomy