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Author Notes:

Email Address:jgooch@emory.edu

The authors acknowledge Hal Franch for helpful discussions and critica eview of the work.

The authors have no financial conflicts of interest to disclose.

Subjects:

Research Funding:

This project was funded by the NIH/NIDDK DK066422 J.L.G.) and DK50740 (S.R.P.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • CELL BIOLOGY
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • calcineurin
  • cyclosporine
  • diabetes
  • renal hypertrophy
  • SKELETAL-MUSCLE HYPERTROPHY
  • GROWTH-FACTOR-BETA
  • CARDIAC-HYPERTROPHY
  • IN-VIVO
  • EXPRESSION
  • INHIBITION
  • ALPHA
  • ACCUMULATION
  • ACTIVATION
  • PATHWAY

Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney

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Journal Title:

Journal of Cellular and Molecular Medicine

Volume:

Volume 15, Number 2

Publisher:

, Pages 414-422

Type of Work:

Article | Final Publisher PDF

Abstract:

Calcineurin is an important signalling protein that regulates a number of molecular and cellular processes. Previously, we found that inhibition of calcineurin with cyclosporine reduced renal hypertrophy and blocked glomerular matrix expansion in the diabetic kidney. Isoforms of the catalytic subunit of calcineurin are reported to have tissue specific expression and functions. In particular, the β isoform has been implicated in cardiac and skeletal muscle hypertrophy. Therefore, we examined the role of calcineurin β in diabetic renal hypertrophy and glomerular matrix expansion. Type I diabetes was induced in wild-type and β -/- mice and then renal function, extracellular matrix expansion and hypertrophy were evaluated. 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. Loss of β did not alter diabetic renal dysfunction assessed by glomerular filtration rate, urine albumin excretion and blood urea nitrogen. Similarly, matrix expansion in the whole kidney and glomerulus was not different between diabetic wild-type and β -/- mice. In contrast, whole kidney and glomerular hypertrophy were significantly reduced in diabetic β -/- mice. Moreover, β -/- renal fibroblasts demonstrated impaired phosphorylation of Erk1/Erk2, c-Jun N-terminal kinases (JNK) and mammalian target of rapamycin (mTOR) following stimulation with transforming growth factor-β and did not undergo hypertrophy with 48 hrs culture in high glucose. 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. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Copyright information:

© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

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