Potential protective action of pituitary adenylate cyclase-activating polypeptide (PACAP38) on in vitro and in vivo models of myeloma kidney injury

• Published in: Blood Vol. 107; no. 2; pp. 661 - 668
• Main Authors: Arimura, Akira, Li, Min, Batuman, Vecihi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-01-2006
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Bone Marrow - metabolism; Cell Adhesion; Chemokine CCL2 - metabolism; Dexamethasone - pharmacology; Immunoglobulin Light Chains - adverse effects; In Vitro Techniques; Interleukin-6 - metabolism; Kidney - drug effects; Kidney - injuries; Male; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Animal; Multiple Myeloma - drug therapy; Multiple Myeloma - etiology; Multiple Myeloma - metabolism; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - therapeutic use; Pituitary Adenylate Cyclase-Activating Polypeptide - genetics; Pituitary Adenylate Cyclase-Activating Polypeptide - metabolism; Pituitary Adenylate Cyclase-Activating Polypeptide - therapeutic use; Protective Agents - metabolism; Protective Agents - therapeutic use; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - genetics; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Stromal Cells - cytology; Stromal Cells - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-03-1186

The most common type of renal injury in multiple myeloma is chronic tubulointerstitial nephropathy associated with casts in tubule lumens, an entity referred to as “myeloma kidney” that often progresses to end-stage kidney diseases. Myeloma kidney is associated with a significant increase in all-cause mortality, yet no effective intervention, except a limited use of steroid, is available. Here, we report that pituitary adenylate cyclase-activating polypeptide with 38 residues (PACAP38) dramatically prevents injury of cultured renal proximal tubule cells caused by myeloma light chains through suppression of proinflammatory cytokines production, by inhibiting p38 MAPK and translocation of NFκB via both PAC1 and VPAC1 receptors. The suppressive effects of PACAP was as effective as dexamethasone in all of their cytokine assays and demonstrated both in vitro and in vivo. Furthermore, PACAP38 inhibits myeloma cell growth directly and may also indirectly by suppressing production of the growth factor, IL-6, from bone marrow stromal cells, that is stimulated by adhesion of myeloma cells. These findings render PACAP38 worth evaluation as a promising candidate for an effective and safe renoprotectant in myeloma kidney, and possibly other nephropathy, and also as a new antitumor agent in multiple myeloma.