Association of serum nitrate and nitrite levels with longitudinal assessments of disease activity and damage in systemic lupus erythematosus and lupus nephritis

Abstract

Objective. Reactive intermediate production is an essential component of the innate immune response that is induced during disease activity in murine lupus. This study was undertaken to determine whether a marker of systemic nitric oxide (NO) production correlates with prospectively studied disease activity in human systemic lupus erythematosus (SLE) and lupus nephritis patients.Methods. Eighty-three SLE patients and 40 control subjects were studied longitudinally. The SLE group included 23 patients with lupus nephritis documented by renal biopsy and 26 with a history of lupus nephritis. During each visit, following a 24-hour lownitrate diet, traditional markers of disease activity and damage were determined. Serum nitrate plus nitrite (NOx) levels were determined by chemiluminescence detection.Results. NOx levels were higher in SLE patients than in controls during the first visit. In univariate longitudinal analyses, NOx levels were associated with SLE Disease Activity Index scores. In multivariate analyses, NOx levels were associated with serum levels of C3 and creatinine and the urinary protein:creatinine ratio. Among patients with lupus nephritis, those with proliferative lesions had higher NOx levels, and higher NOx levels were associated with accumulation of renal damage and lack of response to therapy.Conclusion. This is the first study to prospectively demonstrate longitudinal associations between serum NOx levels and markers of SLE and lupus nephritis disease activity. The more pronounced association with proliferative lupus nephritis and with longitudinal response to lupus nephritis therapy provides a rationale for the study of reactive intermediates as biomarkers of disease activity and therapeutic targets in proliferative lupus nephritis.A common feature in the broad phenotype of systemic lupus erythematosus (SLE) is autoantibody production, a function primarily of the acquired immune system (1). However, an inappropriately active innate immune response is implicated in both the initiation and the pathogenic consequences of autoantibody production in SLE. An important antimicrobial factor in the innate immune response is the production of reactive oxygen and nitrogen intermediates (RONI), including superoxide and nitric oxide (NO) (2).In murine models of lupus, NO production has been shown to increase with the progression of renal disease. Pharmacologic inhibition of inducible NO synthase (iNOS) in these models significantly reduced both NO and reactive oxygen intermediate (ROI) production and also reduced inflammatory glomerular lesions, without affecting the deposition of immunoglobulin or complement (2,3). These findings suggest that iNOS activity or products of iNOS such as superoxide and NO contribute to the proliferative glomerular lesions in murine lupus nephritis and that their production is distal to immune complex deposition and complement activation. Cross-sectional studies of NO production in human SLE have demonstrated increased levels of markers of sys-

NADPH oxidase and nitric oxide synthase-dependent superoxide production is increased in proliferative lupus nephritis

“…Our laboratory and others demonstrated that inducible nitric oxide synthase expression was increased in PLN (3, 4) and that inducible nitric oxide synthase- and myeloperoxidase-mediated modifications of proteins (nitrotyrosine (NTyr)) were increased in the serum of lupus patients with LN, particularly among African-Americans (5). However, the importance of increased inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) production in LN was questioned when genetic deletion of functional iNOS in lupus mouse models failed to reduce the onset of classic pathologic features of LN except vasculitis (6, 7).…”

Renal Glycosphingolipid Metabolism Is Dysfunctional in Lupus Nephritis

“…32 All volunteers gave documented informed consent to participate in Institutional Review Board-approved protocols. Analyzed samples were from patients (predominantly African Americans) meeting American College of Rheumatology revised criteria for SLE 33 without nephritis, subjects with active LN at entry, 32 and control subjects without autoimmune or inflammatory disease. Spot urine and blood collections and clinical evaluations were performed at entry.…”

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

“…Mesangial cells, such as macrophages, produce nitric oxide (NO), superoxide, and other inflammatory mediators in response to LPS, IFN-c and IL1b. [20][21][22] We and others [23][24][25][26] have reported iNOS expression in renal tissue of lupus patients and evidence of nitrated proteins in kidneys from MRL/lpr mice. In addition to NO, other inflammatory mediators released by mesangial cells have a pathogenic role in lupus (i.e.…”