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 beta isoform has been implicated in cardiac and skeletal muscle hypertrophy. Therefore, we examined the role of calcineurin beta in diabetic renal hypertrophy and glomerular matrix expansion. Type I diabetes was induced in wild-type and beta(-/-) mice and then renal function, extracellular matrix expansion and hypertrophy were evaluated. The absence of beta 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 beta 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 beta(-/-) mice. In contrast, whole kidney and glomerular hypertrophy were significantly reduced in diabetic beta(-/-) mice. Moreover, beta(-/-) 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-beta and did not undergo hypertrophy with 48 hrs culture in high glucose. In conclusion, loss of the beta 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 beta appears to be a central mechanism involved in organ hypertrophy.