Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and its pathway involved.

This study investigated if IL6 influenced ECM protein production by MCs and the regulatory pathways involved. Experiments were carried out in cultured human MCs (HMCs) and in mice. We found that overexpressing IL6 and its receptor decreased the abundance of fibronectin and collagen IV in MCs. Enzyme-linked immunosorbent assay and immunoblot analysis demonstrated that thapsigargin (an activator of store-operated Ca2+ entry, SOCE), but not endoplasmic reticular stress inducer tunicamycin, significantly increased IL6 content. This thapsigargin effect was abolished by GSK-7975A, a selective inhibitor of SOCE, and by silencing Orai1 (the channel protein mediating SOCE). Furthermore, inhibition of NFκB pharmacologically and genetically significantly reduced SOCE-induced IL6 production. Thapsigargin also stimulated the nuclear translocation of p65 subunit of NFκB. Moreover, MCs overexpressing IL6 and its receptor in HMCs increased the content of the receptor for glucagon-like peptide-1 (GLP-1R), and IL6 inhibition of fibronectin was attenuated by the GLP-1R antagonist, exendin 9-39. In agreement with the HMC data, specific knockdown of Orai1 in MCs using the targeted nanoparticle delivery system in mice significantly reduced glomerular GLP-1R level. Taken together, our results suggest a novel SOCE/NFкB/IL6/GLP-1R signaling pathway which inhibits ECM protein production by MCs. PMID: 32390515 [PubMed - as supplied by publisher]
Source: American Journal of Physiology. Renal Physiology - Category: Physiology Authors: Tags: Am J Physiol Renal Physiol Source Type: research