Major Vault Protein Promotes Kidney Inflammation and Macrophage Recruitment in a Murine Model of AKI

Background: Acute kidney injury (AKI) is characterized by deterioration of kidney function and increased risk of developing chronic kidney disease (CKD). AKI-to-CKD transition following acute injury results from maladaptive repair leading to renal tubular loss, chronic inflammation and kidney fibrosis. We previously demonstrated that major vault protein (MVP) contributed to kidney inflammation and fibrosis in murine models of CKD. This study investigated the role of MVP in AKI and AKI-to-CKD transition. Methods: MVP expression was assessed using immunocytochemical staining in kidney biopsies from patients with active proliferative lupus nephritis, acute tubular injury, pauci-immune ANCA-associated renal vasculitis or kidney allograft dysfunction. AKI was induced in wild-type (WT) and MVP-knockout (KO) mice by a single dose of folic acid (250 mg/ kg) in 0.3 M sodium bicarbonate administered by intra-peritoneal injection. Mice were sacrificed after 7 days and kidneys harvested for investigation of histopathology and expression of mediators relating to tubular injury and inflammation. Mice administered 0.3 M sodium bicarbonate served as non-AKI Control. Results: MVP was weakly expressed in normal human kidney specimens, but its expression was markedly increased in proximal renal tubular epithelial cells in kidney biopsies of patients with AKI. In WT AKI mice, MVP gene expression was increased by 5.85±1.22-fold compared to WT non-AKI Control mice (p<0.0001), and was accompanied by increased serum urea level, tubular atrophy, macrophage recruitment and increased expression of mediators of tubular injury and inflammation including KIM-1, NGAL, TNF-α, IL-1β, CCL2 and CCL5 (p<0.01, for all). MVP KO mice subjected to induction of AKI showed less severe kidney histopathological features with reduced macrophage infiltration and serum urea level and decreased expression of mediators of tubular injury and inflammation (p<0.05, for all). Conclusion: Our data suggest that MVP contributes to tubulo-interstitial inflammation and tubular injury in murine folic acid-induced AKI, which may modulate AKI-to-CKD transition. Funding: Government Support – Non-U.S.