KAP degradation by calpain is associated with CK2 phosphorylation and provides a novel mechanism for cyclosporine A-induced proximal tubule injury

• Published in: PloS one 2011-09, Vol.6 (9), p.e25746
• Main Authors: Tornavaca, Olga, Sarró, Eduard, Pascual, Gloria, Bardaji, Beatriz, Montero, M Angeles, Salcedo, M Teresa, Plana, Maria, López-Hellin, Joan, Itarte, Emilio, Meseguer, Anna
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Androgens; Animals; Biology; Calpain; Calpain - metabolism; Casein kinase II; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - metabolism; Cell injury; Cell Line; Chronic kidney failure; Cyclosporine - toxicity; Cyclosporins; Cytokines; Cytotoxicity; Damage prevention; Degradation; Enzyme Activation - drug effects; Gene Expression Regulation - drug effects; Hypotheses; Immunosuppression; Injury prevention; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - enzymology; Kidney Tubules, Proximal - injuries; Kidney Tubules, Proximal - metabolism; Kidneys; Kinases; Medicine; Mice; Mice, Transgenic; Molecular Sequence Data; Phosphorylation; Phosphorylation - drug effects; Protein binding; Protein kinase C; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein Processing, Post-Translational - drug effects; Proteins; Proteins - chemistry; Proteins - genetics; Proteins - metabolism; Rodents; Serine; Substrate Specificity; Threonine; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0025746

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA.