SOCS1 Peptidomimetic Alleviates Glomerular Inflammation in MsPGN by Inhibiting Macrophage M1 Polarization.

Abstract

Mesangial proliferative glomerulonephritis (MsPGN), the most common pathological change in primary glomerulonephritis, is characterized by increased macrophage infiltration into glomeruli, which results in proinflammatory cytokine release. Macrophage infiltration and differentiation are induced by the Janus kinase 2 and signal transducer and activator of the transcription 1 (JAK2/STAT1) pathway. As a suppressor of cytokine signaling 1 (SOCS1) downregulates the immune response by inhibiting the JAK2/STAT1 pathway, we investigated whether a peptide mimicking the SOCS1 kinase inhibitor region, namely, SOCS1 peptidomimetic, protects against nephropathy. Glomerular JAK2/STAT1 pathway activation was synchronized with kidney injury in an MsPGN rat model. Rats treated with the SOCS1 peptidomimetic exhibited reduced pathological glomerular changes and lessened macrophage recruitment. Moreover, in vivo, the phosphorylation of the JAK2/STAT1 pathway was downregulated in infiltrated macrophages of glomeruli. In vitro, the SOCS1 peptidomimetic inhibited macrophage M1 polarization by suppressing JAK2/STAT1 activation. In conclusion, our study demonstrated that the SOCS1 peptidomimetic plays a protective role against pathologic glomerular changes in MsPGN by reducing macrophage infiltration and inhibiting macrophage polarizing to the M1 phenotype. SOCS1 peptidomimetic, therefore, presents a feasible therapeutic strategy to alleviate renal inflammation in MsPGN.