Analysis of Molecular Events Occurring after Kidney Donation Reveals Involvement of ADAM9-driven EMT

 

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Analysis of Molecular Events Occurring after Kidney Donation Reveals Involvement of ADAM9-driven EMT

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Naser B.N.
Shehab
Naser B.N. Shehab n.b.n.shehab@umcg.nl University Medical Center Groningen Department of Internal Medicine Groningen Netherlands * Bernoulli Institute for Mathematics, Computer Science and Artificial Intelligence Faculty of Science Engineering Groningen Netherlands Brigham and Women’s Hospital Department of Internal Medicine Boston United States
Stephan J.L. Bakker s.j.l.bakker@umcg.nl University Medical Center Groningen Department of Internal Medicine Groningen Netherlands -
Rudolf S.N. Fehrmann r.s.n.fehrmann@umcg.nl University Medical Center Groningen Department of Medical Oncology Groningen Netherlands -
Martin H. de Borst m.h.de.borst@umcg.nl University Medical Center Groningen Department of Internal Medicine Groningen Netherlands -
 
 
 
 
 
 
 
 
 
 
 

Living kidney donation is an important source of kidneys for transplantation in many countries of the world. After donation, the remaining kidney undergoes adaptive remodeling. Little is known about the early molecular events that govern this adaptive remodeling. We aimed to gain more insight in these early molecular events.

We performed whole-blood transcriptomic analysis on a cohort of 31 living kidney donors with paired measurements at pre- and 3-months post-donation. We used a systems-biology approach to construct stable transcriptional components (TCs), which are statistically independent latent gene expression programs. These TCs were learned by consensus-independent component analysis, trained on a large compendium of publicly available expression profiles from the ARCHS4 database. Donor transcriptomic data were preprocessed uniformly and were then projected onto the derived TCs. TCs were characterized and mapped onto biological pathways using Gene Set Enrichment Analysis (GSEA). Paired t-tests within a multivariate permutation testing framework were used to assess statistical significance of differential activation post-donation. False discovery rate (FDR) was controlled at 0.05 to account for multiple testing.

We analyzed 31 donors with paired whole-blood samples. Age was 57 ± 11 years, 68% were male, and baseline eGFR was 108 ± 19 mL/min/1.73m2. In total, 1262 stable TCs were constructed. Permutation-based, FDR-controlled statistical tests yielded three TCs with altered activation post-donation (Figure 1): TC366 (upregulated, p-value <0.001), TC304 (downregulated, p-value <0.001), and TC719 (downregulated, p-value <0.001). TC366 was driven by the gene ADAM9 and enriched for epithelial-mesenchymal transition (EMT) and adipogenesis pathways. This pro-fibrotic activation was accompanied with downregulation of programs associated with apical junction integrity and myogenesis captured by TC719 and TC304, respectively.


Figure 1. Transcriptional components underlying early post-donation adaptation. (A) Hallmark pathway enrichment for the three significantly altered TCs. (B) Gene-TC associations shown as signed –log10(p) from Spearman correlations; left axis shows Ensembl IDs, right axis HGNC symbols. (C) Boxplots of TC activities pre- vs post-donation for each of the TCs.


Our findings reveal a systemic transcriptional signature in response to unilateral nephrectomy that indicates the initiation of an adaptive remodeling program driven by an ADAM9-dependent EMT pathway. Further research is required to investigate how long it takes for this response to resolve and whether unsuccessful resolution has any long-term consequences.

Kewords