Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes
Katsuhito Ihara, Eiichiro Satake, Parker C. Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I. Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M. Dreyfuss, Monika A. Niewczas, Alessandro Doria, Robert G. Nelson, Marcus G. Pezzolesi, Benjamin D. Humphreys, Kevin Duffin, Andrzej S. Krolewski
Katsuhito Ihara, Eiichiro Satake, Parker C. Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I. Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M. Dreyfuss, Monika A. Niewczas, Alessandro Doria, Robert G. Nelson, Marcus G. Pezzolesi, Benjamin D. Humphreys, Kevin Duffin, Andrzej S. Krolewski
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Research Article Nephrology

Circulating proteins linked to apoptosis processes and fast development of end-stage kidney disease in diabetes

Abstract

Many circulating proteins are associated with risk of ESKD, but their source and the biological pathways/disease processes they represent are unclear. Using OLINK proteomics platform, concentrations of 455 proteins were measured in plasma specimens obtained at baseline from 399 individuals with diabetes. Elevated concentrations of 46 circulating proteins were associated (P < 1 × 10–5) with development of ESKD (n = 143) during 7–15 years of follow-up. Twenty of these proteins enriched apoptosis/TNF receptor signaling pathways. A subset of 20 proteins (5–7 proteins), summarized as an apoptosis score, together with clinical variables accurately predicted risk of ESKD. Expression of genes encoding the 46 proteins in peripheral WBCs showed no difference between cells from individuals who did or did not develop ESKD. In contrast, plasma concentration of many of the 46 proteins differed by this outcome. In single-nucleus RNA-Seq analysis of kidney biopsies, the majority of genes encoding for the 20 apoptosis/TNF receptor proteins were overexpressed in injured versus healthy proximal tubule cells. Expression of these 20 genes also correlated with the overall index of apoptosis in these cells. Elevated levels of circulating proteins flagging apoptotic processes/TNF receptor signaling pathways — and likely originating from kidney cells, including injured/apoptotic proximal tubular cells — preceded the development of ESKD.

Authors

Katsuhito Ihara, Eiichiro Satake, Parker C. Wilson, Bozena Krolewski, Hiroki Kobayashi, Zaipul I. Md Dom, Joseph Ricca, Jonathan Wilson, Jonathan M. Dreyfuss, Monika A. Niewczas, Alessandro Doria, Robert G. Nelson, Marcus G. Pezzolesi, Benjamin D. Humphreys, Kevin Duffin, Andrzej S. Krolewski

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Figure 4

Results of pathway analysis of 46 ESKD risk–associated proteins.

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Results of pathway analysis of 46 ESKD risk–associated proteins. (A) Clu...
(A) Clusters of enriched pathways by 46 ESKD risk–associated proteins are shown. The functional annotation clustering in DAVID software (version 6.8) was applied for pathway enrichment analysis using the DAVID databases (e.g., GO, KEGG, REACTOME pathways and UniprotKB keywords). The results were obtained using 455 proteins measured on 5 OLINK panels. Similar results were obtained when all 1,012 proteins included in 11 OLINK panels were used as background (data not shown). The geometric mean (in –log scale) of the Expression Analysis Systemic Explorer (EASE) scores (modified Fisher exact P values) were used to rank their biological significance. Four clusters of pathways or terms with EAS E scores of P < 0.01 are shown in the figure as statistically significant. More detailed results are shown in Supplemental Table 2. Result of similar analysis for SOMAscan data are shown in Supplemental Figure 3. (B) Venn diagrams of 46 ESKD risk–associated proteins grouped according to enriched pathways are shown. Twenty proteins referred to as apoptosis/TNF receptor proteins were enriching pathways in clusters 1, 3, and 4 in A. Twenty-six other proteins did not enrich any known pathway. However, 8 of these proteins and all 20 apoptosis/TNF receptor proteins were enriching pathways included in cluster 2 referred to as receptors and membrane proteins. Asterisks indicate proteins found to be associated with sickle cell related kidney disease (18).