Thrombotic microangiopathy is a serious complication of renal transplantation. Besides recurrence of the primary disease (RecTMA) renal transplant-associated thrombotic microangiopathy (rTx-TMA) can emerge de novo by humoral rejection (HR-TMA) or calcineurin inhibitor toxicity (CNI-TMA). These different forms of rTx-TMA require different therapy. Prior analysis showed differential expression of pro- and antithrombotic mRNA transcripts in rTx-TMA. We hypothesized that glomeruli with rTx-TMA might have different glomerular capillary microRNA profiles that might explain the shift in mRNA transcripts contributing to microthrombosis and could also allow etiological differentiation.
Biopsies from 19 transplants with TMA (RecTMA, n=6; CNI-TMA, n=7; HR-TMA, n=6) were compared to 8 control biopsies without any histological signs of TMA or humoral rejection. RNA was isolated from glomeruli of paraffin-embedded biopsies. The expression of selected pro- and antithrombotic mRNA transcripts and microRNA profiles were examined using TaqMan real time PCR. Putative target genes were analyzed in silico. Differentially expressed RNAs were identified with Tukey tests. Correlations between miRNAs and mRNAs were determined with Spearman's test.
Out of 675 examined microRNA four microRNA were differentially expressed: Glomerular miR-150 was overexpressed in both RecTMA and CNI-TMA compared to controls. Glomerular miR-222-3p and miR-223 were overexpressed in all subgroups compared to controls. Glomerular miR-513-3p was downregulated in RecTMA compared to CNI-TMA. miR-150, miR-222-3p and miR-223 correlated inversely with KLF2 and KLF4. miR-513-3p correlated inversely with ADAMTS13.
microRNA could cause alterations in the microvascular expression levels of pro- and antithrombotic mRNA transcripts and may contribute to microthrombosis in rTx-TMA. Particularly miR-223 may affect fibrinolysis through induction of PAI-1 and suppression of tPA via suppression of endothelial protective KLF2. microRNA transcripts identified as possibly relevant for the differential diagnosis and for the pathogenesis of rTx-TMA will be verified in a second, independent cohort and in functional studies.
To cite this abstract in AMA style:Wittig J, Bockmeyer C, Agustian P, Dämmrich M, Zell S, Jindra P, Immenschuh S, Becker J. Glomerular microRNA Expression Profiles in Transplant-Associated Thrombotic Microangiopathy [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/glomerular-microrna-expression-profiles-in-transplant-associated-thrombotic-microangiopathy/. Accessed April 20, 2021.
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