Proliferative lupus nephritis (LN) is marked by increased renal thromboxane (TXA2) production. Targeting the TXA2 receptor or TXA2 synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: 1) TXA2 production in the MRL/MpJ-Tnfrsf6lpr/J (MRL/lpr) model of proliferative lupus nephritis is COX2-dependent, and 2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response, and glomerular pathology.
20 female MRL/lpr and 20 BALB/cJ mice were divided into two equal treatment groups: 1) SC-236, a moderately selective COX2 inhibitor, or 2) vehicle. After treatment from 10 to 20 weeks of age, the effectiveness of inhibition of TXA2 was determined by measuring urine TXB2. Response endpoints measured at 20 weeks of age were renal function (GFR), proteinuria, urine nitrate + nitrite (NOX), and glomerular histopathology.
SC236 therapy reduced surrogate markers of renal TXA2 production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NOX) during therapy were observed. However, the beneficial effect of SC236 therapy on GFR was only transient, and renal histopathology was not improved in late disease.
These data demonstrate that renal TXA2 production is COX2-dependent in murine LN and suggest that NO production is directly or indirectly COX2-dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN.