Calcineurin A-β is required for hypertrophy but not matrix expansion in the diabetic kidney.
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.
Reddy
Ramesh N
RN
Department of Medicine/Division of Nephrology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Knotts
Taylor L
TL
Roberts
Brian R
BR
Molkentin
Jeffery D
JD
Price
S Russ
SR
Gooch
Jennifer L
JL
D000418:Albumins; D000818:Animals; D001806:Blood Urea Nitrogen; D019703:Calcineurin / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D005947:Glucose / Q000494:pharmacology; D006984:Hypertrophy; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000418:Albumins; D050778:NFATC Transcription Factors; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019703:Calcineurin; C557393:protein phosphatase 3, catalytic subunit, beta isoform, mouse; D005947:Glucose