Randall plaques (RPs) can contribute to the formation of idiopathic calcium oxalate (CaOx) kidney stones; however, genes related to RP formation have not been identified. We previously reported the potential therapeutic role of osteopontin (OPN) and macrophages in CaOx kidney stone formation, discovered using genome-recombined mice and genome-wide analyses. Here, to characterize the genetic pathogenesis of RPs, we used microarrays and immunohistology to compare gene expression among renal papillary RP and non-RP tissues of 23 CaOx stone formers (SFs) (age- and sex-matched) and normal papillary tissue of seven controls. Transmission electron microscopy showed OPN and collagen expression inside and around RPs, respectively. Cluster analysis revealed that the papillary gene expression of CaOx SFs differed significantly from that of controls. Disease and function analysis of gene expression revealed activation of cellular hyperpolarization, reproductive development, and molecular transport in papillary tissue from RPs and non-RP regions of CaOx SFs. Compared with non-RP tissue, RP tissue showed upregulation (˃2-fold) of LCN2, IL11, PTGS1, GPX3, and MMD and downregulation (0.5-fold) of SLC12A1 and NALCN (P<0.01). In network and toxicity analyses, these genes associated with activated mitogen-activated protein kinase, the Akt/phosphatidylinositol 3-kinase pathway, and proinflammatory cytokines that cause renal injury and oxidative stress. Additionally, expression of proinflammatory cytokines, numbers of immune cells, and cellular apoptosis increased in RP tissue. This study establishes an association between genes related to renal dysfunction, proinflammation, oxidative stress, and ion transport and RP development in CaOx SFs.
Journal of the American Society of Nephrology : JASN. 2016 Jun 13 [Epub ahead of print]
Kazumi Taguchi, Shuzo Hamamoto, Atsushi Okada, Rei Unno, Hideyuki Kamisawa, Taku Naiki, Ryosuke Ando, Kentaro Mizuno, Noriyasu Kawai, Keiichi Tozawa, Kenjiro Kohri, Takahiro Yasui
Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and Department of Urology, Social Medical Corporation Kojunkai Daido Hospital, Daido Clinic, Nagoya, Japan., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and ., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and Department of Urology, Social Medical Corporation Kojunkai Daido Hospital, Daido Clinic, Nagoya, Japan., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and., Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and.