LATE BREAKING II

A. Dosanjh¹, D.R. Salomon², S. Kurian^2
1Molecular And Experimental Medicine, The Scripps Research Institute, La Jolla/CA/UNITED STATES OF AMERICA, ²Molecular And Experimental Medicine, The Scripps Research Institute, La Jolla/UNITED STATES OF AMERICA

Body: Introduction: Chronic allograft nephropathy (CAN) is a common cause of morbidity and mortality in kidney transplants. The most recognizable finding in CAN is interstitial fibrosis marked by increased extracellular matrix (ECM). In turn, fibrosis is linked to transplant prognosis. Integrins, a family of heterodimeric cell adhesion molecules, mediate cell and ECM interactions and are important in the pathogenesis of acute and chronic rejection. We previously showed that HGF and FGF growth factor pathways are upregulated during progression of CAN. Since integrins regulate growth factor pathways and ECM structure, we studied the expression of specific integrins and the integrin pathway from microarray data done by our own laboratory and from two publically available data sets. Methods: We used 84 kidney biopsies (59 CAN / 25 controls), we processed 33 and the remaining were in the NCBI GEO database. All experiments used Affymetrix HG-U133 Plus 2.0 Gene Chips; BRB Array Tools was used to perform class comparisons for differential expression (p value <0.005). Ingenuity Pathway Analysis (IPA) was used to identify significant canonical pathways (p value <0.05). Results: There were 4861 differentially expressed genes between CAN and control samples. The integrin pathway was significantly expressed in all class comparisons v. control. Among the 200 known genes in the integrin pathway, 12-30%, were significantly differentially expressed as a function of different grades of CAN. Class comparisons of Control (Banff 0) v. CAN samples (any grade) identified β1 and α6 as consistently expressed irrespective of Banff grades. Integrin β6 was uniquely expressed in mild CAN (Banff 0 v. 1), whereas α2 was uniquely expressed in moderate/severe CAN (Banff 0 v. 2+3). There were 51 associated genes from the pathway that were differentially expressed regardless of grade, 18 of which were unique to the 0 v. 1+2+3 comparison including human Arp2/3 protein complex, the Phosphatidylinositol 3-kinase family and the ras homolog gene family. ARF6 a key molecule in signaling pathways that lead to actin remodeling was unique to B1 vs. 2+3, consistent with our recent publication of actin pathway upregulation in CAN by tandem MS proteomics. The results of the integrin subunits are in Table 1.
Conclusions: Our meta-analysis of CAN biopsy samples demonstrates a large number of significantly differentially expressed integrin pathway molecules. These results also mapped functionally to the actin cytoskeleton super-pathway, supporting both literature and our work. While several integrin blocking antibodies have been studied in transplantation, their pleotrophic roles in biology makes it difficult. Thus, if validated in additional cohorts, this significantly expanded list of integrin pathway molecules should be reevaluated for therapeutic targets.

Disclosure: All authors have declared no conflicts of interest.