Calcineurin is activated in diabetes and is required for glomerular hypertrophy and ECM accumulation.
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.
Gooch
Jennifer L
JL
South Texas Veterans Health Care Administration, Audie Murphy Memorial Hospital, San Antonio 78284-3900, USA. Gooch@UTHSCSA.edu
Barnes
Jeffrey L
JL
Garcia
Sergio
S
Abboud
Hanna E
HE
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006984:Hypertrophy; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000235:genetics
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D005353:Fibronectins; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; C120817:calcineurin phosphatase; D019703:Calcineurin; D010744:Phosphoric Monoester Hydrolases