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

Abstract

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 cyclaseactivating 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 NFB via both PAC 1 and VPAC 1 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. ( IntroductionMultiple myeloma is the sixth most common cancer in the United States. About 13 200 new cases of multiple myeloma were diagnosed in 2000. According to the US Renal Data System, renal morbidity from multiple myeloma is substantial. 1 Myeloma kidney disease was associated with 250% increase in all-cause mortality. 1 The kidney is vulnerable to pathogenic effects of monoclonal light chains in multiple myeloma and other disease associated with overproduction of immunoglobulin light chains. 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 disease. 2,3 Although the mechanisms of cast formation have been clarified in studies that showed that certain types of light chains behave as ligand binding to defined sites on Tamm-Horsfall proteins, 4 the mechanisms responsible for chronic tubulointerstitial injury have only recently been explored. 5,6 These studies showed that increased endocytosis and overloading by myeloma light chains in proximal tubule cells produce inflammatory cytokines. These cytokine responses were mediated by activation of nuclear factor NFB and signaled through MAPKs, ERK1/2, JNK, and p38 MAPK. Despite improved understanding of the pathophysiology, no effective treatment is known for myeloma kidney except for a limited use of steroids.Pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) was isolated from ovine hypothalamic tissues based on the ability to stimulate adenylate cyclase in pituitary cell cultures. 7 PACAP38 is a new member of the vasoactive intestinal peptide (VIP) family of peptides. It is...

The effects of pituitary adenylate cyclase activating polypeptide in renal ischemia/reperfusion

“…Increase of the level of TNF-α both in the plasma and in the kidney could be counteracted by PACAP treatment [28,30]. several studies have reported the protective effect of pacap in myeloma nephropathy [2,3,[25][26][27]. Among others, PACAP was able to reduce TNF-α and IL-6 expression as well as the morphological damage of tubular cells.…”

Pituitary Adenylate Cyclase–Activating Polypeptide Stimulates Renin Secretion via Activation of PAC1 Receptors

“…However, the isolated perfused kidney is still a complex model in which renin release can be influenced by several other indirect factors, such as the endothelium and changes of tubular function. Because both PACAP type 1 and PACAP type 2 receptors are expressed in tubular cells (12), it seemed plausible that the stimulation of renin release by PACAP might have been related to changes in tubular function. Therefore, we performed experiments using isolated renin-producing cells.…”

“…Therefore, PACAP induces vasodilation in several vessel types and vascular beds such as coronary, cerebral, and pulmonary arteries; arteries of the skin; hindquarters; and the uteroplacental circulation (4 -10). Moreover, PACAP increases renal blood flow in conscious rats (11) and bears protective effects on myeloma injury of proximal tubular cells (12), providing functional links between PACAP and the kidney. A possible role of PACAP in kidney function has also been suggested by the detection of PACAP-binding sites and PACAP receptor gene expression in the kidney (12)(13)(14)(15)(16)(17).…”

Lymphangiogenesis Is Upregulated in Kidneys of Patients With Multiple Myeloma

“…Potential therapeutic strategies for improving renal function are chemotherapy, with or without subsequent autologous stem cell transplantation, and extended dialysis with protein-leaking dialyzers (Hutchison et al, 2007). According to in vitro and in vivo data (Arimura et al, 2006), the application of the pituitary adenylate cyclase-activating polypeptide could be a promising alternative in the future.…”