title: KAP degradation by calpain is associated with CK2 phosphorylation and provides a novel mechanism for cyclosporine A-induced proximal tubule injury.
abstract: 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.
authors: Fisiopatologia Renal, Centre d'Investigacions en Bioquímica i Biologia Molecular (CIBBIM), Institut de Recerca Vall d'Hebron, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors: Olga
authors: O
authors: Tornavaca
authors: Eduard
authors: E
authors: Sarró
authors: Gloria
authors: G
authors: Pascual
authors: Beatriz
authors: B
authors: Bardaji
authors: M Angeles
authors: MA
authors: Montero
authors: M Teresa
authors: MT
authors: Salcedo
authors: Maria
authors: M
authors: Plana
authors: Joan
authors: J
authors: López-Hellin
authors: Emilio
authors: E
authors: Itarte
authors: Anna
authors: A
authors: Meseguer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D016572:Cyclosporine / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: C067670:Kap protein, mouse; D047428:Protein Kinase Inhibitors; D011506:Proteins; D016572:Cyclosporine; D047390:Casein Kinase II; D002154:Calpain