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Genes Expressed by Both Mesangial Cells and Bone Marrow–Derived Cells Underlie Genetic Susceptibility to Crescentic Glomerulonephritis in the Rat

Jennifer Smith^*, Ping-Chin Lai, Jacques Behmoaras, Candice Roufosse, Gurjeet Bhangal^*, John P McDaid^*, Timothy Aitman, Frederick WK Tam^*, Charles D. Pusey^* and H. Terence Cook

^* Section of Renal Medicine, Department of Histopathology and Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Imperial College London, London, United Kingdom; and Kidney Institute, Department of Nephrology, School of Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taipei, Taiwan

Address correspondence to: Prof. H. Terence Cook, Department of Histopathology, Hammersmith Campus, Imperial College London, Du Cane Road, London, W12 0NN, UK. Phone: +44-20-8383-2009; Fax: +44-20-8383-814l; E-mail: t.cook{at}imperial.ac.uk

Received for publication July 13, 2006. Accepted for publication March 29, 2007.

The Wistar-Kyoto (WKY) rat shows marked susceptibility to crescentic glomerulonephritis. In the model of nephrotoxic nephritis (NTN) that is induced by a small dose of nephrotoxic globulin, WKY rats developed crescents in 80 ± 2% of glomeruli at day 10, whereas no crescents were seen in Lewis rats. This was associated with marked increase in monocyte chemoattractant protein-1 synthesis in WKY glomeruli. It was posited whether susceptibility depended on circulating cells or intrinsic renal cells. Bone marrow (BM) isografts from WKY to WKY or Lewis to Lewis did not affect susceptibility to NTN. When BM was transferred from WKY to Lewis rats, crescents developed in 35 ± 9% of glomeruli 10 d after induction of NTN, indicating that susceptibility could be transferred by BM cells. However, crescents were also seen in WKY rats that were given Lewis marrow. For assessment of the contribution of intrinsic renal cells, kidneys from WKY or Lewis rats were transplanted into F1 animals. In NTN, the ratio of crescents in the transplanted kidney to the native kidney was significantly higher for WKY-to-F1 than for Lewis-to-F1 transplants, demonstrating that the kidney itself also influences susceptibility. Mesangial cell responses were then examined in the two strains. Mesangial cells that were derived from WKY rats synthesized significantly more monocyte chemoattractant protein-1 basally and after stimulation with heat-aggregated rabbit IgG or TNF-. These results show that susceptibility to NTN in the WKY rat depends on both circulating and intrinsic renal cells and that there are genetic differences between the strains in mesangial responses to inflammatory stimuli.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673