It is critical to uncover genes specifically expressed in individual cell types for further understanding of cell biology and pathology. with the hope to offer new therapeutic strategies has stimulated the development of megsin inhibitors by a structure based drug design approach relying on Rabbit Polyclonal to MRPS18C a precisely known three dimensional megsin structure assays utilizing recombinant megsin indeed confirmed that megsin serves as a functional serpin [7]. EXPRESSIONS OF MEGSIN ONT-093 IC50 GENE AND PROTEIN IN THE KIDNEY Northern blot and reverse-transcribed polymerase chain reaction analyses of various tissues and cells exhibited that megsin was predominantly expressed in human mesan-gial cells [4]. These findings were further confirmed by hybridization and by immunohistochemistry (Fig. ?(Fig.1)1) using megsin-specific antibodies [4, 8, 9]. In IgA nephropa-thy and diabetic nephropathy, megsin mRNA expression in glomeruli was up-regulated. A similar up-regulation of meg-sin was observed in the experimental anti-Thy1 nephritis model of ONT-093 IC50 rats [10]. The increased expression of megsin gene is usually thus associated with renal disorders with mesangial proliferation and its matric accumulation. Fig. (1) Megsin protein expression in the kidney glomerulus. Immunofluorescence study utilizing anti-human megsin demonstrates that megsin is usually predominantly localized in the glomerulus, especially in the mesaigial area ( 200). GENOMIC ASSOCIATION OF MEGSIN WITH KIDNEY DISEASE Recent studies have exhibited the interesting association of the polymorphisms of megsin gene with susceptibility and/or progression of kidney disease in Chinese patients [11C13]. The correlation between polymorphisms of megsin gene and IgA nephropathy were investigated by using the family-based association study. Polymorphisms C2093T and C2180T within the 3 untranslated region of megsin were first examined. Transmission disequenlibrium test (TDT) and haplotype relative risk (HRR) analyses revealed that megsin 2093C and 2180T alleles were significantly more transmitted from heterozygous parents to patients, which suggested that this genetic variation in ONT-093 IC50 megsin conferred susceptibility to IgA nephropathy [11]. To further examine the associations of these genetic variants with clinical manifestations and renal histological lesions, haplotypes were constructed by using the C2093T and C2180T alleles. The genotype-phenotype relationship study found that the 2093C-2180T haplotype is usually associated with more severe forms of IgA nephropathy and more rapid disease progression [12]. It raised the question that whether these two variants confer the effect or just in linkage disequilibrium with other variants nearby. To answer this question, 12 known SNPs from different functional regions of megsin were selected from GenBank. The genotypes were determined by PCR-RFLP and direct sequencing and the heterozygosis rates were calculated if the genotypes were heterozygote. When the rate exceeded 10 %10 %, the TDT and HRR analysis were performed. We found two novel SNPs which hadnt been reported ONT-093 IC50 before (23179 9T/10T and 23103 7A/6A), and six heterozygous SNPs, among which five SNPs with the rate more than 10 %10 % were analyzed. TDT and HRR analyses showed that 23167G alleles were transmitted more frequently from parents to patients than expected. The scores of glomerular index and glomerular sclerosis index were higher in GG genotype patients than those in other genotypes and the distribution frequency of GG genotype in the progressive group was higher than that of the stable group. The polymorphism of megsin A23167G is usually thus associated with susceptibility and progression of IgA nephropa-thy in Chinese populace. GG genotype is usually associated with severe histological lesions and progression of the disease [13]. The ONT-093 IC50 analysis of other four SNPs found no statistical significance. These data suggest the possible involvement of genetic variations of megsin in the susceptibility and progression of IgA nephropathy. PATHOBIOLOGICAL FUNCTION OF MEGSIN To further understand a pathobiological role of megsin, we overexpressed the human megsin cDNA in mouse ge-nome [7]. Two lines of megsin transgenic mice have been obtained. They developed progressive mesangial matrix accumulation, an increase in the number of mesangial cells (proliferation), and an augmented immune complex deposition (Figs. ?(Figs.22A and B). The transgenic model is usually characterized by the expression of megsin in all tissues due to the ubiquitous promoter for the transgene. Although immunohisto-chemical studies revealed the presence of megsin in a host of tissues as well as in non-mesangial areas of the kidney, pathogenic effects of megsin overexpression were restricted within glomeruli. The mechanism of glomerular abnormalities still remains unknown. We speculate that overexpression of megsin, a novel serpin expressed in the glomerulus, may lead to mesangial dysfunction, impair the disposal of immune complexes, and increase mesangial matrix by tipping the balance towards lower matrix degradation. By contrast, histological abnormalities were not evident.