Novel Serpinopathy in Rat Kidney and Pancreas Induced by Overexpression of Megsin

Inagi, Reiko; Nangaku, Masaomi; Usuda, Nobuteru; Shimizu, Akira; Onogi, Hiroshi; Izuhara, Yuko; Nakazato, Kiyokazu; Ueda, Yoshimichi; Oishi, Hisashi; Takahashi, Sumio; Yamamoto, Masayuki; Suzuki, Daisuke; Kurokawa, Kiyoshi; Strihou, Charles van Ypersele de; Miyata, Toshio

doi:10.1681/asn.2004070600

Cited by 27 publications

(26 citation statements)

References 30 publications

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“…Previous reports by our and other groups have emphasized a pathogenic role of ER stress in glomerular and tubular epithelial injury. 14,17,20,21 Immunohistochemical analysis in this study showed upregulation of the ER chaperones GRP78 and ORP150 in the glomeruli of rats with antiThy1 nephritis. Furthermore, activation of the PERK pathway, a UPR pathway involved in the downregulation of translation, was also detected in the glomeruli of these rats.…”

Section: Discussionsupporting

confidence: 49%

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

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106

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Accumulating evidence suggests a pathophysiologic role of endoplasmic reticulum (ER) stress in kidney disease. This study investigated the potential of therapeutic approaches targeting ER stress in the anti-Thy1 model of mesangioproliferative glomerulonephritis in rats. Immunohistochemistry and Western blotting showed a time-dependent increase in the expression of the ER stress-inducible chaperones glucose-regulated protein 78 (GRP78) and oxygen-related protein 150 in isolated glomeruli, especially in the glomerular epithelial cells and mesangial cells, after induction of anti-Thy1 nephritis. For evaluation of whether preconditioning with ER stress ameliorates the severity of disease, rats were pretreated with a subnephritogenic dose of the ER stress inducer tunicamycin or thapsigargin for 4 d before disease was induced. Although preconditioning with ER stress had no effect on the degree of disease induction, it strongly ameliorated the manifestations of disease, evidenced by marked reductions in microaneurysm formation, mesangial proliferation, and adhesion of Bowman's capsule to the glomerular tuft. This improvement in histologic damage was associated with reduced proteinuria (39.4 Ϯ 10.5 versus 126.1 Ϯ 18.1 mg/d; P Ͻ 0.01) and with attenuated increases in glucose-regulated protein 78 and oxygen-related protein 150 expression. Of note, pretreatment with tunicamycin or thapsigargin decreased the excessive ER stress-induced intracellular signaling observed in anti-Thy1 nephritis. In conclusion, preconditioning with ER stress ameliorates the severity of disease in rats with anti-Thy1 nephritis. These findings suggest the possibility of therapeutic approaches targeting ER stress in mesangioproliferative glomerulonephritis.

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Section: Discussionsupporting

confidence: 49%

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Inagi

Kumagai

Nishi

et al. 2008

Journal of the American Society of Nephrology

Self Cite

106

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“…We have previously observed polymers in COS-7 cells transfected with M a 1 -antitrypsin (E.M. and D.A.L., unpublished results) whereas others have reported the polymerization of the wild-type serpin megsin when expressed at high levels. 28 These results demonstrate that the 2C1 mAb recognizes polymers formed by different disease associated variants of a 1 -antitrypsin, including Z and a range of shutter domain mutants.…”

Section: Resultsmentioning

confidence: 68%

A Novel Monoclonal Antibody to Characterize Pathogenic Polymers in Liver Disease Associated with α1-Antitrypsin Deficiency†

et al. 2010

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Alpha 1 -antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes the protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This causes neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. We have developed a conformation-specific monoclonal antibody (2C1) that recognizes the pathological polymers formed by a 1 -antitrypsin. This antibody was used to characterize the Z variant and a novel shutter domain mutant (His334Asp; a 1 -antitrypsin King's) identified in a 6-week-old boy who presented with prolonged jaundice. His334Asp a 1 -antitrypsin rapidly forms polymers that accumulate within the endoplasmic reticulum and show delayed secretion when compared to the wild-type M a 1 -antitrypsin. The 2C1 antibody recognizes polymers formed by Z and His334Asp a 1 -antitrypsin despite the mutations directing their effects on different parts of the protein. This antibody also recognized polymers formed by the Siiyama (Ser53Phe) and Brescia (Gly225Arg) mutants, which also mediate their effects on the shutter region of a 1 -antitrypsin. Conclusion: Z and shutter domain mutants of a 1 -antitrypsin form polymers with a shared epitope and so are likely to have a similar structure. (HEPATOLOGY 2010;52:1078-1088 T he serpinopathies are conformational diseases characterized by the polymerization and intracellular retention of members of the serine protease inhibitor or serpin superfamily of proteins.1 The best known is a 1 -antitrypsin deficiency, with the most common severe deficiency allele being the Z mutation (Glu342Lys). This mutation results in the retention of ordered polymers of a 1 -antitrypsin as periodic acid Schiff positive inclusion bodies within the endoplasmic reticulum (ER) of hepatocytes.2 These inclusions predispose the individual homozygous for the Z variant of the a 1 -antitrypsin protease inhibitor (PI*Z) to neonatal hepatitis, cirrhosis, and rarely, hepatocellular carcinoma.3 Deficiency of circulating a 1 -antitrypsin results in early onset panlobular emphysema.

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“…Megsin, a mesangial-cell-specific serine protease inhibitor, is known to be induced during the progression of glomerular injury and to participate in the pathogenesis of mesangial nephritis (32). Notably, we found that the G3YR mouse kidneys showed significantly increased expression of megsin in the glomerular cell fraction (Fig.…”

Section: B125-g3mentioning

confidence: 69%

Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect

Moriguchi

Otsuki

et al. 2016

Molecular and Cellular Biology

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bGATA3 is a zinc finger transcription factor that plays a crucial role in embryonic kidney development, while its precise functions in the adult kidney remain largely unexplored. Here, we demonstrate that GATA3 is specifically expressed in glomerular mesangial cells and plays a critical role in the maintenance of renal glomerular function. Newly generated Gata3 hypomorphic mutant mice exhibited neonatal lethality associated with severe renal hypoplasia. Normal kidney size was restored by breeding the hypomorphic mutant with a rescuing transgenic mouse line bearing a 662-kb Gata3 yeast artificial chromosome (YAC), and these animals (termed G3YR mice) survived to adulthood. However, most of the G3YR mice showed degenerative changes in glomerular mesangial cells, which deteriorated progressively during postnatal development. Consequently, the G3YR adult mice suffered severe renal failure. We found that the 662-kb Gata3 YAC transgene recapitulated Gata3 expression in the renal tubules but failed to direct sufficient GATA3 activity to mesangial cells. Renal glomeruli of the G3YR mice had significantly reduced amounts of platelet-derived growth factor receptor (PDGFR), which is known to participate in the development and maintenance of glomerular mesangial cells. These results demonstrate a critical role for GATA3 in the maintenance of mesangial cells and its absolute requirement for prevention of glomerular disease.

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Novel Serpinopathy in Rat Kidney and Pancreas Induced by Overexpression of Megsin

Cited by 27 publications

References 30 publications

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

Preconditioning with Endoplasmic Reticulum Stress Ameliorates Mesangioproliferative Glomerulonephritis

A Novel Monoclonal Antibody to Characterize Pathogenic Polymers in Liver Disease Associated with α1-Antitrypsin Deficiency†

Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect

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