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β-Arrestins are multifunctional proteins originally identified as negative adaptors of G protein-coupled receptors (GPCRs). Emerging evidence has also indicated that β-arrestins can activate signaling pathways independent of GPCR activation. This study was to elucidate the role of β-arrestins in diabetic nephropathy (DN) and hypothesized that β-arrestins contribute to diabetic renal injury by mediating podocyte autophagic process. We first found that both β-arrestin-1 and β-arrestin-2 were upregulated in the kidney from streptozotocin-induced diabetic mice, diabetic db/db mice and kidney biopsies from diabetic patients. We further revealed that either β-arrestin-1 or β-arrestin-2 deficiency (Arrb1−/− or Arrb2−/−) ameliorated renal injury in diabetic mice. In vitro, we observed that podocytes increased both β-arrestin-1 and β-arrestin-2 expression levels under hyperglycemia condition and further demonstrated that β-arrestin-1 and β-arrestin-2 shared common mechanisms to suppress podocyte autophagy by negative regulation of ATG12–ATG5 conjugation. Collectively, this study for the first time demonstrates that β-arrestin-1 and β-arrestin-2 mediate podocyte autophagic activity, indicating that β-arrestins are critical components of signal transduction pathways that link renal injury to reduce autophagy in DN. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with DN.

LncRNA is reported to have important role in diabetic nephropathy (DN). Here, we aim to identify key lncRNAs of DN using bioinformatics and systems biological methods. Method: Five microarray data sets from Gene Expression Omnibus (GEO) database were included. Probe sets were re-annotated. In the training set, differential expressed genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was constructed to screen diabetic-related hub genes and reveal their potential biological function. Two more human data sets and mouse data sets were used as validation sets. Results: A total of 424 DEGs, including 10 lncRNAs, were filtered in the training data set. WGCNA and enrichment analysis of hub genes showed that inflammation and metabolic disorders are prominent in DN. Three key lncRNAs (NR_130134.1, NR_029395.1 and NR_038335.1) were identified. These lncRNAs are also differently expressed in another two human data sets. Functional enrichment of the mouse data sets showed consistent changes with that in human, indicating similar changes in gene expression pattern of DN and confirmed confidence of our analysis. Human podocytes and mesangial cells were culture in vitro . QPCR and fluorescence in situ hybridization were taken out to validate the expression and relationship of key lncRNAs and their related mRNAs. Results were also consistent with our analysis. Conclusions: Inflammation and metabolic disorders are prominent in DN. We identify three lncRNAs that are involved in these processes possibly by interacting with co-expressed mRNAs.

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