Interstitial HIF1A induces an estimated glomerular filtration rate decline through potentiating renal fibrosis in diabetic nephropathy

Abstract Aims This study aimed to identify interstitial molecules that are responsible for the deterioration of the esiantimated glomerular filtration rate (eGFR) in DN. Materials and methods Weighted gene co-expression network analysis (WGCNA) was used to link the tubulointerstitial gene expression profile of DN to the eGFR values. The relationship of eGFR with each sub-domain regulator in the network was analyzed with the linear regression model. Gene sets enrichment analysis (GSEA) was applied to detect the molecular changes mostly relating to the essential regulators. Key findings Four co-expression modules were found strongly correlating with eGFR values. Genes from these modules were over-represented in fibrosis-related biological processes (extracellular matrix (ECM) organization and cell adhesion) and pathways (integrin signaling and ECM-receptor interaction). Of sub-domains in the gene interaction network, the expression of hypoxia-inducible factor 1A (HIF1A) was most negatively correlated with eGFR (R2 = 0.417, P = 0.026). The positive correlations between HIF1A and its target genes were found, indicating an enhanced transcriptional activity of HIF1A. We also found that HIF1A positively correlated with CCAAT enhancer binding protein delta (CEBPD) (r = 0.731, P = 0.011), an activator of HIF1A transcription. Moreover, GSEA showed that high HIF1A expression was enriched with fibrosis associated signaling like ECM-receptor interaction and cell adhesion. Intriguingly, VEGFA expression decreased while HIF1A increased (R2 = 0.733, P = 0.001), suggesting VEGFA loss may exacerbate hypoxia and constitute a stimulus to HIF1A induction. Significance The present study suggests that interstitial HIF1A may be involved in the pathogenesis of renal interstitial fibrosis in DN.