Compensatory renal hypertrophy following uninephrectomy is calcineurin-independent

• Type of Material: Article
• Authors: Clintoria Williams, Emory University; Brandi M Wynne, Atlanta Veterans Administration Medical Center; Makeeva Walker, Emory University; Robert Hoover Jr, Emory University; Jennifer Gooch, Emory University
• Language: English
• Date: 2014-12-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2014 The Authors.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1111/jcmm.12438
• Title of Journal or Parent Work: Journal of Cellular and Molecular Medicine
• ISSN: 1582-1838
• Volume: 18
• Issue: 12
• Start Page: 2361
• End Page: 2366
• Grant/Funding Information: Funding for this project was provided by the American Physiological Society STEP-UP program (MW), National Institutes of Health/NIDDK T32 DK00756 (CRW and BMW), National Institutes of Health R01 DK-085097 and Research Service, Atlanta VA Medical Center (RSH), and the Department of Veterans Affairs MERIT program (JLG).
• Keywords: renal hypertrophy; GROWTH-FACTOR-BETA; calcineurin; Life Sciences & Biomedicine; DEPENDENT MECHANISM; Research & Experimental Medicine; NFAT; NADPH OXIDASE; DIABETIC KIDNEY; EXPRESSION; ALPHA-ISOFORM; Medicine, Research & Experimental; uninephrectomy; Science & Technology; cyclosporin; CYCLOSPORINE-A; INDUCED CARDIAC-HYPERTROPHY; MICE; A-BETA; Cell Biology
• Research Categories: Health Sciences, General

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.