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Wani, Javid (2005): Nitric oxide modulates the expression of matricellular genes involved in fibrosis in renal glomerular mesangial cells. Dissertation, LMU München: Medizinische Fakultät



By means of their proliferative and secretory potential glomerular mesangial cells are thought to be important mediators of glomerular inflammation and fibrosis. Recent studies have established a direct role for NO in the regulation of gene expression in different cell types including mesangial cells. Representational difference analysis was used to investigate changes in gene expression elicited by the treatment of S-Nitroso-L-glutathione in rat mesangial cells. We identified 7 upregulated and 11 downregulated genes. Four out of 11 downregulated genes, connective tissue growth factor, thrombospondin-1, collagen type I alpha 1 and collagen type I alpha 2, are matricellular genes linked to inflammation and fibrosis of different organs including the kidney. Results were verified by using Northern blot analysis, quantitative real time PCR and protein analysis methods in human mesangial cells treated with a series of NO donors. We validated our findings by inducing endogenous NO production by cytokine stimulation. Real time PCR analysis showed that two additional matrix related genes, biglycan and collagen type IV alpha 2 are also downregulated by NO. Connective tissue growth factor promoter studies in mesangial cells demonstrated that NO acts at the transcriptional level to suppress gene expression. These results reveal a complex role of NO in regulating gene expression in mesangial cells and suggest an antifibrotic potential for NO.