A Single Genetic Mutation Changes Mouse Lupus Molecular Abnormalities

ObjectiveGenetic factors play a key role on development of systemic lupus erythematosus(SLE) and lupus nephritis (LN). Nonetheless, to date, relationship between geneticschange and SLE and LN remains unclear. To demonstrate effect of single geneticmutation on SLE and LN, we investigate Faslprmice and Fas+mice, of which geneticbackground was identical, but Fas genetic type was different. We detected theexpression and distribution of Molecular markers such as MMPs, CXCR4and IL-11in SLE mice using organs in vitro and in vivo. Furthermore, we also measuredexpression of these markers in renal pathological issue, urine and serum plasm toevaluate mechanisms and effects of single genetic mutation on SLE and LN.Methods1.Ten MRL/MpJ-Faslpr/J mice and tem their MRL/MpJ counterparts in SPF level(male, age2-4months, The Jackson Laboratory，Bar Harbor, ME)2.All mice were divided into two groups: Experiment group (A group,MRL/MpJ-Faslpr/J mice) and control group (B group, MRL/MpJ mice). In addition,all mice in two groups were assigned into2,3,4months subgroups according age.3.Expression and distribution of MMPs, CXCR4, IL-11in two SLE groups weredetected using small animal model in vivo imaging; expression of MMP-2、MMP-9、ds-DNA、C3and urine protein and Scr were measured with ELISA in mice withdifferent age. Renal pathological tissue was evaluated by HE; expression of MMP-2,MMP-9and CXCR4in mice kidney were observed using immunohistochemistry.ResultMMP signal was mainly observed in kidney in Faslprmice, which wassignificantly higher than that in Fas+mice using small animal model in vivo imaging(P<0.01); Expression of IL-11in lung tissue of Faslprmice was significantly highlythan that in Fas+mice (P<0.01), but was significantly lower in kneet-joint(P<0.05);CXCR4signal in liver in Faslprmice was significantly lower than that in Fas+ mice(P<0.01).Expression of ds-DNA in Faslprmice was significantly highly than that in Fas+mice (P<0.01); C3in Faslprand Fas+mice in2months was significantly higher ascompared to that in those with4months(FaslprP=0.0136; Fas+P=0.0218). urinealbumin and Scr was increased with mice age(Alb FaslprP=0.0279, Fas+P=0.0309;UCr FaslprP=0.0001, Fas+P=0.0043). Similar trends were observed in albumincreatinine ration (ACR, FaslprP=0.0395; Fas+P=0.0307).Expression of MMP-2in Faslprmice with2months was significantly highly thanthat in their counterparts (P<0.05), and strikingly increased with age(P<0.01);expression of MMP-9also increased with age(P<0.01).Immunohistochemistryshowed that MMP-9in Faslprmice was strikingly increased with age.ConclusionsIn SLE model mice with identical genetic background, but different Fas genetictype, MMP and IL-11were observed in kidney and lung in Faslprmice; IL-11andCXCR4were showed in joint and liver in Fas+mice. These findings suggested thatFaslprmay contribute to kidney and lung injury, whereas Fas+may prone to developjoint injury. Our results demonstrated that single genetic mutation pays a role ondevelopment and complexity of SLE.C3levels were remarkably higher in Faslprand Fas+mice with2months, butstrikingly lower in4months. Urine albumin and Scr levels increased with age, andurine albumin in Faslprmice was higher compared with Fas+mice. ACR significantlyincreased with age in Faslprmice compared with Fas+mice. Severed crescentricdevelopment was observed in kidney in Faslprmice with4months, but mildmesangial cell and matrix proliferation was shower in kidney in Fas+mice with4months. Showed that SLE duration was similar in Faslprand Fas+mice, and severerkidney injury was observed in Faslpras compared to Fas+mice. These findingsfurthermore found that single genetic mutation play a paramount role on SLE and LN.MMP-2levels increased, but MMP-9decreased with age in Faslprand Fas+mice,which suggested that MMP-2and MMP-9involves in development of SLE and maybe considered as specific diagnosis marks.