The mechanism of renal cell apoptosis involves transcriptional activation of the inducible nitric oxide synthase (iNOS) gene by nuclear factor (NF)-kappa B. The role of apoptosis in mediating tubulointerstitial injury in human lupus nephritis (LN) remains unclear. We examined the relationship between alterations in NF-kappa B activation and iNOS expression levels and the degree of apoptosis in both glomerular and tubulointerstitial compartments of subjects with LN. Studies were done in renal biopsies front 49 patients with LN and 10 normal kidney tissues. Apoptotic and proliferating cells were identified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and staining with anti-proliferating cell nuclear antigen antibody, respectively. Nuclear factor-kappa B and iNOS expression was examined by Southwestern histochemistry and immunohistochemistry, respectively. Glomerular cell apoptosis and proliferation increased concomitantly in LN. Glomerular apoptosis correlated with the activity index, the degree of proliferation, and the level of glomerular overexpression of iNOS and activated NF-kappa B in LN. Tubular cell apoptosis correlated with the activity and chronicity indices, the degree of tubular atrophy, and decline in renal function at the time of biopsy. Tubular expression of iNOS and activated NF-kappa B correlated with tubular cell proliferation in LN. Nuclear factor kappa B activation accompanied overexpression of iNOS in both glomerular and tubulointerstitium compartments in LN. Apoptosis of renal cells associated with NF-kappa B activation and iNOS overexpression may play an important role in mediating chronic renal injury, especially tubulointerstitial lesions that may manifest clinically as progressive renal insufficiency. (c) 2006 Elsevier Inc. All rights reserved.