Functional and structural changes in end-stage kidney disease due to glomerulonephritis induced by the recombinant alpha3(IV)NC1 domain.
The aim of this study was to develop and characterize a rat glomerulonephritis model, which progresses to renal fibrosis and renal failure. A single immunization of female WKY rats with more than 10 microg of recombinant alpha3(IV)NC1 protein caused severe proteinuria followed by progressive increases in plasma creatinine and blood urea nitrogen (BUN) level within 42 days. Sequential histopathological evaluation revealed crescent formation in glomeruli followed by tubular dilation and interstitial fibrosis. Hydroxyproline content and expression of type I collagen and smooth muscle actin genes in the renal cortex increased as renal dysfunction progressed. Furthermore, the TGF-beta1 level in the renal cortex also increased. In the evaluation of antinephritic agents in this model, prednisolone and mycophenolate mofetil (MMF) treatment significantly decreased plasma creatinine and BUN, and suppressed renal fibrosis and histological changes involving crescent formation, compared with the vehicle-treated nephritic rats, whereas lisinopril treatment failed to improve renal function and histology. We demonstrated that immunization of female WKY rats with a sufficient dose of recombinant alpha3(IV)NC1 induces end-stage kidney disease accompanied by renal fibrosis. The relatively short period needed to induce the disease and the high incidence of functional and structural changes were considered a great advantage of this model for clarifying the mechanisms of progressive glomerulonephritis and for evaluating agents used to treat renal failure.
Nishibayashi
Seiji
S
Quests Research Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Hattori
Katsuji
K
Hirano
Takahiro
T
Uehara
Kenji
K
Nakano
Yoshimasa
Y
Aihara
Miki
M
Yamada
Yoshihisa
Y
Muraguchi
Masahiro
M
Iwata
Fusako
F
Takiguchi
Yoshiharu
Y
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000009:adverse effects*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024141:Collagen Type IV / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005921:Glomerulonephritis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006909:Hydroxyproline / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007677:Kidney Function Tests; D017706:Lisinopril / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011239:Prednisolone / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D011994:Recombinant Proteins / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D001324:Autoantigens; D024042:Collagen Type I; D024141:Collagen Type IV; D003404:Creatinine; D006909:Hydroxyproline; D007166:Immunosuppressive Agents; D017706:Lisinopril; D009173:Mycophenolic Acid; D011239:Prednisolone; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C498862:Acta2 protein, rat; C057112:type IV collagen alpha3 chain