Calcineurin A (Ca) Inhibition Supresses Protein Synthesis Via Amp Dependent Kinase (Ampk).

• Main Authors: H. Franch (Author), C. Ding (Author), S. Zoromsky (Author), S. Williams (Author), J. Gooch (Author)
• Format: Book
• Published: The Korean Society of Nephrology, 2012-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Diabetes stimulates CA activity in the kidney and CA inhibitor cyclosporine A (CYA) or CAβ isoform knock-out (CAβ -/-) block diabetic renal hypertrophy.CA regulates the mammalian target of rapamycin (mTOR) to reduce protein synthesis (PS) during cardiac hypertrophy.To study this pathway, NRK-52E and SV40 transformed CAβ +/+ and -/- proximal tubule cell lines were treated with 10 nM epidermal growth factor (EGF) and/or 8 μM CYA. After 48 hrs of CYA in NRK-52E cells, EGF-induced protein/well was 30±4% lower with decreased PS (49±2%) rather than increased protein breakdown. In CAβ -/- cells, protein/well (20+2%) and PS (16 ±1%) were lower and CYA did not decrease PS further. In CAβ+/+ cells, CYA reduced PS 20+2%. However, CYA did not block mTOR signaling as measured by phosphorylation (P) at S2448 or by p70S6 kinase P at T389. CYA also did not alter the mTOR dependent pathway of macroautophagy. However, CYA in NRK-52E or CAβ -/- cells showed increased activation of the metformin-sensitive energy sensor, AMPK, as measured by P of T172 by ∼5- or>10-fold, respectively. AMPK reduces PS via P of eukaryotic elongation factor 2 (eEF2) at T356 and CYA increased eEF2 P by∼3 fold.We conclude CA inhibition reduces PS in renal hypertrophy via a novel pathway involving AMPK and eEF2 rather than by mTOR and p70S6 kinase. Activation of AMPK or altered energy metabolism via CAβ may be important in CA inhibitor nephrotoxicity.

Item Description

2211-9132
10.1016/j.krcp.2012.04.380