Neutralization of Macrophage-Stimulating Protein Ameliorates Renal Injury in Anti–Thy 1 Glomerulonephritis

Abstract

Macrophage-stimulating protein (MSP) is a scatter factor that causes cell proliferation and migration, and receptor origin nantaise (RON) is its receptor. RON is expressed in macrophages and mesangial cells, and MSP is produced by renal tubular cells. This study investigated whether MSP/RON participate in the pathogenesis of anti-Thy 1 nephritis, a glomerular disease that is characterized by invasion of circulating monocytes into glomeruli and migration and proliferation of mesangial cells. In vivo, renal function and histopathology were studied in rats that had anti-Thy 1 disease and were untreated and treated with a neutralizing anti-MSP antibody. In vitro, whether monocytes express RON and whether MSP has a chemotactic effect on monocytes were studied. In vivo, in anti-Thy 1 disease, MSP was expressed de novo in glomeruli, and neutralization of MSP attenuated the rise in serum creatinine and proteinuria, stopped glomerular neutrophil and monocyte influx, protected from glomerular injury, and lessened mesangial cell overgrowth. M acrophage-stimulating protein (MSP) is a "scatter factor" that is homologous to hepatocyte growth factor (HGF) (1-3). The receptor of MSP is receptor origin nantaise (RON), a proto-oncogene product (4). Information on the cell source of MSP and the biologic meaning of the MSP/RON system is very limited. Originally, MSP was described as a serum factor produced by hepatocytes that enhanced the chemotactic response of macrophages to the C5a fraction of complement (5-8). It was then demonstrated that MSP induces proliferation, migration, and invasive growth of keratinocytes and epithelial tumor cell lines. These findings have suggested a role of MSP in skin-wound healing and in oncogenesis (8 -15).We have shown that MSP is diffusely expressed in tubular epithelium of human kidney and that proximal tubular cells release MSP. In addition, we have shown that human mesangial cells express RON and that MSP induces in human mesangial cell growth, migration, invasion into an artificial collagen matrix, and synthesis of IL-6 (16). These findings suggest that MSP, either circulating or as paracrine product, may participate in the pathogenesis of mesangial proliferative glomerulonephritis (e.g., by inducing mesangial cell proliferation, movement, and invasion into the subendothelial space). An additional mechanism of glomerular endocapillary proliferation that may be induced by MSP is the recruitment of circulating monocytes into the glomerulus. In fact, MSP has a chemoattractant action on macrophages that are derived from monocytes. As yet, however, we ignore whether circulating monocytes express RON, and indeed the role of MSP in the pathogenesis of glomerulonephritis or any else inflammatory disease has never been investigated.This study was performed to understand whether the MSP/ RON system plays a pathogenic role in mesangial proliferative glomerulonephritis. We investigated MSP/RON in anti-Thy 1 glomerulonephritis because in this experimental disease, both proliferation of resident mesangial...

Mesenchymal stromal cells improve renal injury in anti-Thy 1 nephritis by modulating inflammatory cytokines and scatter factors

“…described previously [18]; group B, 25 rats were injected vtv at day 0 with 400 μg of anti-Thy 1.1 mAb, followed after 3 days by injection vtv of 1 ml of PBS containing 3 × 10 6 MSC isolated from EGFP rats; group C, 20 rats were injected vtv at day 0 with 400 μg of anti-Thy 1.1 mAb, followed after 3 days by injection vtv of 3 × 10 6 rat mesangial cells; group D, 20 rats were injected vtv at day 0 with 400 μl of saline, followed at day 3 by injection vtv of 1 ml of PBS containing 3 × 10 6 MSC isolated from EGFP rats; and group E, 20 rats were injected vtv with 400 μl of saline. Five rats from each group were killed at day 1, 7, 10 and 14, and five rats from group B were killed 12 h after MSC infusion.…”

MSP: An emerging player in metabolic syndrome

“…MSP also has proliferative effects. Accordingly, neutralization of MSP could relieve the observed proliferation of glomerular cells in nephritis [5], thus partly protecting the glomerulus from damage. Moreover, MSP is reported to participate in the pathological processes of rheumatoid arthritis [61] and peritonitis [62], where MSP showed disease-inhibiting action in both.…”

“…Importantly, with MSP treatment, the gentamicin-induced renal inflammation could be attenuated [59]. In a rodent model with anti-Thy 1 nephritis -a well-established experimental model of mesangial proliferative nephritis, neutralization of MSP by using anti-MSP antibody, however, results in attenuated infiltration of the inflammatory cells, decreased plasma creatinine and proteinuria, and eventually protects glomerular from injury [5]. It is noteworthy that this nephritis is most commonly caused by autoimmune-disorders.…”

“…MSP was later shown to be involved in inflammatory responses and following studies demonstrated MSP to be a crucial regulator of inflammation in multiple animal disease models of the liver, kidney, lung, gut and other organs [2][3][4][5]. Studies showed that homozygous MSP knockout mice (MSP À/À mice) were viable without any obvious abnormalities, however they developed hepatic steatosis even fed on normal chow diet [6].…”

Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells

“…On the other hand, MSP induces superoxide anion production, leading to respiratory burst in human macrophages [17]. MSP neutralization is also protective against glomerular injury in anti-Thy 1 glomerulonephritis by inhibiting monocyte recruitment and reducing inflammation [18]. Thus, future investigations must define the physiological role of MSP/RON and its molecular mechanisms in kidney diseases.…”