Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation

Am J Physiol Renal Physiol. 2003 Jan;284(1):F144-54. doi: 10.1152/ajprenal.00158.2002. Epub 2002 Sep 11.

Abstract

Diabetic nephropathy is characterized by the rapid onset of hypertrophy and ECM expansion. Previously, we showed that calcineurin phosphatase is required for hypertrophy and ECM synthesis in cultured mesangial cells. Therefore, we examined the effect of calcineurin inhibition on renal hypertrophy and ECM accumulation in streptozotocin-induced diabetic rats. After 2 wk of diabetes, calcineurin protein was increased in whole cortex and glomeruli in conjunction with increased phosphatase activity. Daily administration of cyclosporin A blocked accumulation of both calcineurin protein and calcineurin activity. Also associated with calcineurin upregulation was nuclear localization of the calcineurin substrate NFATc1. Inhibition of calcineurin reduced whole kidney hypertrophy and abolished glomerular hypertrophy in diabetic rats. Furthermore, calcineurin inhibition substantially reduced ECM accumulation in diabetic glomeruli but not in cortical tissue, suggesting a differential effect of calcineurin inhibition in glomerular vs. extraglomerular tissue. Corresponding increases in fibronectin mRNA and transforming growth factor-beta mRNA were observed in tubulointerstitium but not in glomeruli. In summary, calcineurin plays an important role in glomerular hypertrophy and ECM accumulation in diabetic nephropathy.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcineurin / metabolism*
  • Calcineurin Inhibitors
  • Cyclosporine / pharmacology
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / metabolism*
  • Diabetic Nephropathies / pathology*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology*
  • Fibronectins / genetics
  • Gene Expression / drug effects
  • Hypertrophy
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology*
  • Male
  • Phosphoric Monoester Hydrolases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Transforming Growth Factor beta / genetics

Substances

  • Calcineurin Inhibitors
  • Enzyme Inhibitors
  • Fibronectins
  • Transforming Growth Factor beta
  • Cyclosporine
  • calcineurin phosphatase
  • Calcineurin
  • Phosphoric Monoester Hydrolases