Unraveling the Intrakidney Gene Network Underlying the Association of EFNA4 and Kidney Disease Progression

Le résumé fourni par la source

Background: Circulating proteins of the axon guidance pathway (AGP) have been linked to kidney disease progression. However, the molecular mechanisms remain unclear. We aim to identify intra-kidney signaling cascades mediating the association between AGPs and kidney disease progression Methods: We analyzed kidney transcriptome from micro-dissected glomerular (n=39) and tubular samples (n=41),correlating them with circulating AGP levels in CKD patients from the C-PROBE cohort. Genes significantly correlated with AGP proteins were used to create an AGP kidney-signature score (KSS). A cox-regression model was used to determine the association between circulating EFNA4 and disease progression(ESKD/40% loss in baseline GFR).A ligand-receptor analysis in kidney single-cell data from the Kidney Precision Medicine Project identified predominant EFNA4 receptors using the Connectome method. KSS scores using the ssgsea method were calculated for cell types with enriched receptor expression in DKD (n=14) and living donors (LD) (n=20). Receptor protein level was determined using western blot analysis. Results: Higher circulating EFNA4 levels were associated with an increased risk of progression (HR=3.6 [1.4-9.1], p=0.007) in CKD patients (N=83). EFNA4 was associated with 82 intrarenal transcripts (FDR <0.05). It was enriched in canonical pathways beyond just the Ephrin receptor signaling and fibrosis pathways. The EFNA4 KSS, derived from intrarenal gene expression, was higher in CKD patients compared to LD (p<0.0001), correlated with circulating EFNA4 (r=0.39), baseline GFR(r=-0.51), and associated with progression in C-PROBE patients (p=0.003). In single-cell kidney biopsy analysis, EPHA7, an EFNA4 receptor, showed increased expression in proximal tubular (PT) cells of DKD patients, paralleling an increase in the EFNA4-KSS. PT cells expressing EPHA7 had higher EFNA4-KSS scores than those without, indicating dependency on EPHA7. EPHA7 protein demonstrated higher level in patients with CKD compared to LDs. Conclusion: Our study linked increased circulating EFNA4 with receptor EPHA7 and EFNA4-KSS, indicating EFNA4 is associated with worse outcomes in CKD patients. These findings suggest EFNA4 and EPHA7 as potential therapeutic targets for mitigating kidney disease progression in CKD patients. Funding: NIDDK Support

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.