Identification of biomarkers and drug repurposing candidates based on an immune-, inflammation- and membranous glomerulonephritis-associated triplets network for membranous glomerulonephritis

Abstract

Background: Membranous glomerulonephritis (MGN) is a common kidney disease. Despite many evidences support that many immune and inflammation-related genes could serve as effective biomarkers and treatment targets for MGN patients, the potential associations among MGN-, immune-and inflammation-related genes have not been sufficiently understood. Methods: Here, a global immune-, inflammation-and MGN-associated triplets (IIMATs) network is constructed and analyzed. An integrated and computational approach is developed to identify dysregulated IIMATs for MGN patients based on expression and interaction data. Results: 45 dysregulated IIMATs are identified in MGN by above method. Dysregulated patterns of these dysregulated IIMATs are complex and various. We identify four core clusters from dysregulated IIMATs network and some of these clusters could distinguish MGN and normal samples. Specially, some anti-cancer drugs including Tamoxifen, Bosutinib, Ponatinib and Nintedanib could become candidate drugs for MGN based on drug repurposing strategy follow IIMATs. Functional analysis shows these dysregulated IIMATs are associated with some key functions and chemokine signaling pathway. Conclusions: The present study explored the associations among immune, inflammation and MGN. Some effective candidate drugs for MGN were identified based on immune and inflammation. Overall, these comprehensive results provide novel insights into the mechanisms and treatment of MGN.

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“…Moreover, the safety of Bosutinib from the immunological point of view is supported by the quite total absence of infective adverse events [67]. Moreover, in a model of membranous glomerulonephritis, Bosutinib was able to ameliorate renal damage by reducing expression of IL2R, IL4R, and by inhibiting JAK2/JAK3 (that sustain the inflammatory pathway) [68]. In another murine model of intra-cerebral hemorrhage with brain injury caused by post-bleeding inflammation, Bosutinib once more showed its anti-inflammatory action: inhibiting SIK-2, it activates CREB and IkB, so blocking the NF-kB-derived inflammation.…”

The Efficacy of Cyclophosphamide Combined with Prednisone in Membranous Nephropathy Patients with Different Cytochrome P450 2B6 Gene Polymorphisms and Analysis of Factors Influencing the Efficacy

“…It is typically characterized by immune complex deposition under the glomerular basement membrane epithelium with diffuse thickening of the basement membrane visible on light microscopy, and with granular, diffuse IgG and complement C3 along the capillary wall seen by immunofluorescence, and with the deposition of subepithelial granular electron-dense material seen by electron microscopy. 12 Currently, clinical treatment of MN includes non-immunosuppressive symptomatic supportive therapy (control of blood pressure, reduction of urinary protein levels, application of angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, etc. ), glucocorticoids and immunosuppressive therapy.…”

Mechanisms of Primary Membranous Nephropathy

“…For instance, the binding of aTHSD7A-Ab to cell expressing THSD7A affects the cytoskeleton [ 19 ]. Considering that PMN is a kidney-limited autoimmune disease, alterations in the global immune-, inflammation-, and MGN (membranous glomerulonephritis)-associated triplet (IIMATs) networks were recently identified, which include chemokine signaling, the Jak-STAT pathway, B cell and T cell signaling pathways, and others [ 62 ], highlighting the importance of abnormalities in immune processes to MN pathogenesis.…”