EXPRESSION SIGNATURES OF EXTRACELLULAR MATRIX RELATED TRANSCRIPT SETS LINKED RENAL ALLOGRAFT INTERSTITIAL FIBROSIS/TUBULAR ATROPHY WITH ACUTE T-CELL MEDIATED REJECTION
Silke Rödder1, Andreas Scherer2, Hans-Peter Marti1. 1University of Bern, Inselspital Bern, Department of Nephrology and Hypertension, Switzerland; 2Spheromics, Kontiolahti, Finland.
Renal allograft T cell-mediated acute rejection (AR) and interstitial fibrosis / tubular atrophy (IF/TA) commonly share excessive extracellular matrix remodelling, which is regulated by the Zn-protease family of metzincins, including matrix metalloproteases, tissue inhibitors of metalloproteases and their related genes.
Metzincins (METS, n=81) and metzincins and related genes (MARGS, n=160) were deregulated in renal allograft biopsies with AR (n=10) and IF/TA (n=22), and microarray profiling identified METS and MARGS based AR and IF/TA gene signatures 1, 2.
Here, we illustrate the differences and conformities between AR and IF/TA METS and MARGS signatures applying differential gene expression analyses, together with pathway and biological process analyses. Expression changes of METS and MARGS were also linked to patient histology.
A five-way VENN diagram of all deregulated (log2 fold change vs. Banff Normal 3(N), p<0.05) METS and MARGS in AR, AR+IF/TA, IF/TA (I, II, III) identified 2 METS and 7 MARGS to be commonly deregulated in all patient groups. Interestingly, no gene was solely deregulated in AR. In contrast, 4 MARGS, 1 METS showed unique IF/TAI deregulation and could be associated to renal injury and hypertrophy by Ingenuity Pathway Analyses (IPA). IF/TAII and -III patients showed the greatest number of commonly deregulated genes. 5 MARGS, 1 METS were solely deregulated in IF/TAII, and 34 MARGS, 16 METS in IF/TAIII.
METS and MARGS, deregulated in AR were associated to the canonical pathway “hepatic fibrosis”, and higher expression of METS in our severe and moderate IF/TA patients was significantly associated to the occurrence of AR prior to IF/TA diagnosis.
THBS2, previously identified as IF/TA marker 2 belonged to the top scoring candidates associated to connective tissue disorders, apoptosis and cancer identified by IPA in IFTA. QRT-PCR of microdissected functional kidney compartments showed significant upregulation of THBS2 in proximal tubuli of AR and in glomeruli, proximal tubuli and tubular interstitium of IF/TA patients. Serum ELISA revealed increasing expression of THBS2 comparing AR and IF/TA, both significantly different from N patients.
In conclusion, METS and MARGS expression in IF/TA was linked to AR, and AR THBS2 upregulation may be indicative of IF/TA development.