Abstract
Mesangial cells are glomerular cells of stromal origin. During immune complex mediated crescentic glomerulonephritis (Crgn), infiltrating and proliferating pro-inflammatory macrophages lead to crescent formation. Here we have hypothesised that mesangial cells, given their mesenchymal stromal origin, show similar immunomodulatory properties as mesenchymal stem cells (MSCs), by regulating macrophage function associated with glomerular crescent formation. We show that rat mesangial cells suppress conA-stimulated splenocyte proliferation in vitro, as previously shown for MSCs. We then investigated mesangial cell-macrophage interaction by using mesangial cells isolated from nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) and NTN-resistant Lewis (LEW) rats. We first determined the mesangial cell transcriptome in WKY and LEW rats and showed that this is under marked genetic control. Supernatant transfer results show that WKY mesangial cells shift bone marrow derived macrophage (BMDM) phenotype to M1 or M2 according to the genetic background (WKY or LEW) of the BMDMs. Interestingly, these effects were different when compared to those of MSCs suggesting that mesangial cells can have unique immunomodulatory effects in the kidney. These results demonstrate the importance of the genetic background in the immunosuppressive effects of cells of stromal origin and specifically of mesangial cell-macrophage interactions in the pathophysiology of crescentic glomerulonephritis.
Highlights
Macrophage infiltration plays a crucial role in the development of crescentic glomerulonephritis [1,2,3]
We have previously shown that nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) mesangial cells (MCs) secrete relatively higher levels of MCP-1 when compared with LEW in both basal and TNFa stimulated MCs, suggesting that there is a genetically determined mesangial cell activation [4,7]
‘MSC-educated’ macrophage activation has been proposed by several groups [28,29,30], and recently, transplantation of mesenchymal stem cells promoted an alternative pathway of macrophage activation and functional recovery after spinal cord injury [31]
Summary
Macrophage infiltration plays a crucial role in the development of crescentic glomerulonephritis [1,2,3]. We have been investigating the relative role of MCs and macrophages in the nephrotoxic nephritis (NTN) model of crescentic glomerulonephritis (Crgn) in the Wistar Kyoto (WKY) rat. This inbred rat strain is uniquely susceptible to macrophage-dependant NTN [11]. Bone marrow transplantation studies between the NTNsusceptible WKY and NTN-resistant LEW rats together with mesangial cell activation assays show that resident renal cells account for about 10% of glomerular crescent formation (90% of the Crgn susceptibility is caused by circulating cells). The intrinsic renal contribution may be, in part, due to mesangial cell secretion of MCP-1 upon stimulation with TNF-a [4,7] since WKY cells secrete increased levels of MCP-1 when compared with LEW mesangial cells indicating that there is a genetic predisposition for mesangial cell activation [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
