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Articles in PresS, published online ahead of print September 11, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00158.2002
Submitted on April 25, 2002
Accepted on August 28, 2002
1 Department of Medicine and Nephrology, University of Texas Health Science Center, San Antonio, San Antonio, TX, USA; Audie Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA
* To whom correspondence should be addressed. E-mail: Gooch{at}uthscsa.edu.
Diabetic nephropathy is characterized by the rapid onset of hypertrophy and extracellular matrix (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 (STZ)-induced diabetic rats. After 2 weeks of diabetes, calcineurin protein was increased in whole cortex and glomeruli in conjunction with increased phosphatase activity. Daily administration of cyclosporin A blocked both accumulation of calcineurin protein and calcineurin activity. Also associated with calcineurin up-regulation 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 versus extra-glomerular tissue. Corresponding increases in fibronectin mRNA and TGFß 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.
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