Calcineurin A-ß is required for hypertrophy but not matrix expansion in the diabetic kidney.
J Cell Mol Med
; 15(2): 414-22, 2011 Feb.
Article
in En
| MEDLINE
| ID: mdl-19778355
ABSTRACT
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 ß isoform has been implicated in cardiac and skeletal muscle hypertrophy. Therefore, we examined the role of calcineurin ß in diabetic renal hypertrophy and glomerular matrix expansion. Type I diabetes was induced in wild-type and ß(-/-) mice and then renal function, extracellular matrix expansion and hypertrophy were evaluated. The absence of ß 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 ß 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 ß(-/-) mice. In contrast, whole kidney and glomerular hypertrophy were significantly reduced in diabetic ß(-/-) mice. Moreover, ß(-/-) 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-ß and did not undergo hypertrophy with 48 hrs culture in high glucose. In conclusion, loss of the ß 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 ß appears to be a central mechanism involved in organ hypertrophy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Calcineurin
/
Diabetes Mellitus, Experimental
/
NFATC Transcription Factors
/
Extracellular Matrix
/
Kidney
Limits:
Animals
Language:
En
Journal:
J Cell Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2011
Document type:
Article
Affiliation country:
United States