Mesangial cell injury has a major role in many CKDs. Because renin-positive precursor cells give rise to mesangial cells during nephrogenesis, this study tested the hypothesis that the same phenomenon contributes to glomerular regeneration after murine experimental mesangial injury. Mesangiolysis was induced by administration of an anti-mesangial cell serum in combination with LPS. In enhanced green fluorescent protein-reporter mice with constitutively labeled renin lineage cells, the size of the enhanced green fluorescent protein-positive area in the glomerular tufts increased after mesangial injury. Furthermore, we generated a novel Tet-on inducible triple-transgenic LacZ reporter line that allowed selective labeling of renin cells along renal afferent arterioles of adult mice. Although no intraglomerular LacZ expression was detected in healthy mice, about two-thirds of the glomerular tufts became LacZ positive during the regenerative phase after severe mesangial injury. Intraglomerular renin descendant LacZ-expressing cells colocalized with mesangial cell markers a8-integrin and PDGF receptor-b but not with endothelial, podocyte, or parietal epithelial cell markers. In contrast with LacZ-positive cells in the afferent arterioles, LacZ-positive cells in the glomerular tuft did not express renin. These data demonstrate that extraglomerular renin lineage cells represent a major source of repopulating cells for reconstitution of the intraglomerular mesangium after injury.

Autoantibodies to double-stranded (ds) DNA represent a serological hallmark of systemic lupus erythematosus (SLE) and may critically contribute to the pathogenesis of lupus nephritis. Self-reactive antibodies might be partially produced by long-lived plasma cells (PCs), which mainly reside within the bone marrow and spleen. In contrast to short-lived PCs, long-lived PCs are extremely resistant to therapy and may sustain refractory disease courses. Recently, antibody-secreting cells were found within the inflamed kidneys of New Zealand black/white (NZB/W) F1 lupus mice as well as of patients with SLE. To analyze the longevity of the IgG-producing cells present in nephritic kidneys of NZB/W F1 mice we performed in vivo BrdU-labeling. We identified a higher frequency of long-lived than shortlived renal PCs, indicating that survival niches for long-lived PCs also exist within inflamed kidneys. Using ELISPOT assays, we found that on average 31% of renal IgGproducing cells reacted with dsDNA and 24% with nucleolin. Moreover, the frequencies of IgG-secreting cells specific for the autoantigens dsDNA and nucleolin were higher in the kidneys compared with those in the spleen and bone marrow.

Objective. The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus.Methods. Lupus-like disease in C57BL/6 and TLR-2 ؊/؊ mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay.Results. Pristane-injected TLR-2 ؊/؊ mice generated reduced numbers of splenic CD138؉/cytoplasmic L/L chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wildtype controls. TLR-2 deficiency prevented the pristaneinduced systemic release of interleukin-6 (IL-6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c؉ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2 ؊/؊ mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells.Conclusion. TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE.

BZ and SRL represent promising drugs with anti-humoral activity in the situation of an already established chronic humoral or mixed alloimmune response after renal transplantation.

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