The new complement inhibitor CRIg/FH ameliorates lupus nephritis in lupus-prone MRL/lpr mice

The aberrant activation of complement system is critically involved in lupus nephropathy. Recent study showed complement C3 inhibitor was effective in the treatment of lupus nephropathy. In this study, we investigate the effect of a novel complement C3 inhibitor, CRIg/FH, in the treatment of lupus nephropathy in MRL/lpr lupus mice. We treated MRL/lpr female mice with a dose escalation of CRIg/FH (10, 5 and 2 mg/kg) by intraperitoneal injection twice weekly since 12 weeks age. In addition, MRL/lpr mice treated with intraperitoneal injection of normal saline or oral prednisone, along with C57BL/6 J healthy mice were maintained to serve as controls. We started 8-h urine collection weekly to screen proteinuria by measuring the levels of urine urea/creatinine. Serum samples was collected at week 16 and 20 to measure levels of urea nitrogen, creatinine, and immunological markers (C3, C4, A-ds-DNA) before the mice were sacrificed at 20 weeks age to collect kidneys for histopathological examinations. Overt skin lesions were observed in MRL/lpr mice treated with normal saline, while skin lesion was not observed in CRIg/FH treated MRL/lpr mice. There was no overt proteinuria observed in MRL/lpr mice treated with CRIg/FH. Serum creatinine and BUN levels in MRL/lpr mice was maintained in highest CRIg/FH dose (10 mg/kg twice a week) to be significantly lower than that in prednisone treated MRL/lpr mice at 20 weeks age. In addition, CRIg/FH treatment in MRL/lpr mice results in a significantly elevated serum C3 and C4 levels when compared to prednisone treatment at both 16 and 20 weeks. Furthermore, our study identified that serum level of A-ds-DNA was also significantly lower in CRIg/FH treatment than that in predisone treated MRL/lpr mice. Renal pathology confirmed that kidneys from CRIg/FH treated MRL/lpr mice suffered less from nephritis and complement disposition. Our results showed that the complement inhibitor CRIg/FH can protect MRL/lpr mice from lupus nephropathy by preserving renal function and glomerulus complement activation. Our findings support the positive effect of complement inhibitors in the treatment of lupus nephropathy.