Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney. Export

@article{citeulike:6091296, abstract = {Calcineurin is an important signaling 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 (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 wildtype 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 NFATc activity. Loss of beta did not alter diabetic renal dysfunction assessed by GFR, urine albumin excretion, and blood urea nitrogen (BUN). Similarly, matrix expansion in the whole kidney and glomerulus was not different between diabetic wildtype 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, JNK and mTOR following stimulation with TGFbeta and did not undergo hypertrophy with 48 hours 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.}, author = {Reddy, Ramesh N. and Knotts, Taylor L. and Roberts, Brian R. and Molkentin, Jeffery D. and Price, S. Russ and Gooch, Jennifer L.}, citeulike-article-id = {6091296}, citeulike-linkout-0 = {http://dx.doi.org/10.1111/j.1582-4934.2009.00910.x}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19778355}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19778355}, day = {23}, doi = {10.1111/j.1582-4934.2009.00910.x}, issn = {1582-4934}, journal = {Journal of cellular and molecular medicine}, keywords = {1, akt, calcineurin, dn, erk, hypertrophy, jnk, mtor}, month = {September}, posted-at = {2009-11-10 04:14:54}, priority = {2}, title = {Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney.}, url = {http://dx.doi.org/10.1111/j.1582-4934.2009.00910.x}, year = {2009} }

TY - JOUR ID - citeulike:6091296 L3 - citeulike-article-id:6091296 N2 - Calcineurin is an important signaling 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 (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 wildtype 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 NFATc activity. Loss of beta did not alter diabetic renal dysfunction assessed by GFR, urine albumin excretion, and blood urea nitrogen (BUN). Similarly, matrix expansion in the whole kidney and glomerulus was not different between diabetic wildtype 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, JNK and mTOR following stimulation with TGFbeta and did not undergo hypertrophy with 48 hours 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. JF - Journal of cellular and molecular medicine SN - 1582-4934 TI - Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney. KW - 1 KW - akt KW - calcineurin KW - dn KW - erk KW - hypertrophy KW - jnk KW - mtor AU - Reddy, Ramesh AU - Knotts, Taylor AU - Roberts, Brian AU - Molkentin, Jeffery AU - Price, Russ AU - Gooch, Jennifer PY - 2009/09/23/ UR - http://dx.doi.org/10.1111/j.1582-4934.2009.00910.x ER -