The organ-specific manifestations of systemic lupus erythematosus (SLE) are highly influenced by the inherent characteristics of the vasculature. Although the endothelium normally functions to thwart cell extravasation, at sites of inflammation this living barrier undergoes remarkable phenotypic changes. The overall hypothesis of this proposal is that the endothelial phenotype in SLE patients is substantially altered secondary to increased expression of inducible nitric oxide synthetase (NOS2). A secondary hypothesis is that the NOS2-dependent endothelial phenotype is associated with a procoagulant diathesis which ultimately leads to thrombotic microangiopathy and end-organ injury. The essential link providing the molecular rationale for the proposed study is that the immunomodulatory drug mycophenolate mofetil (MMF), in contrast to cyclophosphamide or azathioprine, interferes with pterin availability to NOS2. The Aspreva Lupus Management Study (ALMS) is a multi-center trial to assess the efficacy of MMF compared to intravenous cyclophosphamide (IVC) in the induction, and MMF vs. azathioprine in the maintenance, of response in lupus nephritis. The major goal of this application is to examine whether the cellular mechanism accounting for the benefit of MMF is due, at least in part, to a restorative effect on the altered endothelium.
Three specific aims are proposed.
In Aim 1, the approach is to enumerate longitudinally serum and urinary levels of NO, and circulating levels of cellular components reflecting endothelial injury and regeneration, and to compare these cellular and metabolite measures with expression of adhesion molecules and NOS2/3 in skin biopsies.
In Aim 2, markers of NOS2-dependent endothelial activation, inflammation, and thrombin activation will be evaluated quantitatively and longitudinally in plasma and urine. Three candidates, sEPCR, IL-18, and (F1+2) prothrombin were selected based on a pathogenic model which describes the involvement of NOS2 in endothelial cell injury and consequent renal damage. A fourth candidate, adiponectin, was chosen as a biomarker that reflects inflammation but may be independent of NO production. These markers will be correlated to immunostains of the skin and renal biopsies.
Aim 3 will relate genetic polymorphisms associated with inflammation, vasoconstrictor responses and coagulation with clinical outcomes following MMF and IVC (Induction Phase) as well as with markers reflecting filtration abnormalities. SNPs in the promoter region/exons for NOS2, NOS3, EPCR, IL-18 and ACE will be examined. The hypothesis being tested is that possession of a SNP may be associated with abnormal eGFR or protein/creatinine ratios, which may in part explain the effectiveness of therapy. Relevance to public health: The association of markers/indices of NOS2 expression with mechanism of action of a successful drug treatment in lupus nephritis would be a major advance.
| Izmirly, Peter M; Shvartsbeyn, Marianna; Meehan, Shane et al. (2012) Dysregulation of the microvasculature in nonlesional non-sun-exposed skin of patients with lupus nephritis. J Rheumatol 39:510-5 |
| Izmirly, Peter M; Barisoni, Laura; Buyon, Jill P et al. (2009) Expression of endothelial protein C receptor in cortical peritubular capillaries associates with a poor clinical response in lupus nephritis. Rheumatology (Oxford) 48:513-9 |
