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1 South Texas Veterans Health Care Administration, Audie Murphy Memorial Hospital, and 2 Renal Division, University of Texas Health Science Center, San Antonio, Texas 78284-3900
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-
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.
extracellular matrix; kidney; cyclosporin A; mesangial cells
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