Role of transforming growth factor‐β/Smad signalling pathway in enhanced production of glomerular extracellular matrix in IgA nephropathy of high‐serum‐IgA ddY mice

Abstract

SUMMARY: The high‐IgA inbred strain (HIGA) of ddY mice, an animal model of human IgA nephropathy, shows consistently high serum IgA levels, progressive mesangial sclerosis and IgA deposition, and elevated renal expression of transforming growth factor (TGF)‐β. In the present study the role of the TGF‐β/Smad signalling pathway in extracellular matrix (ECM) production was assessed in cultured mesangial cells derived from HIGA mice. The production of type I and type IV collagens in response to TGF‐β1, expression of Smad2, Smad4, Smad7, and Sp1 and p300, and phosphorylation of Smad2 by TGF‐β1 were assessed in cultured mesangial cells derived from HIGA mice at the age of 10 weeks by comparison with age‐matched C57BL/6 mice as controls. In addtion, the expression of p300 and type I and type IV collagens in renal tissues of HIGA mice at the age of 60 weeks was determined. The production of type I and type IV collagens by cultured mesangial cells in HIGA mice was markedly upregulated compared with that in C57BL/6 mice. Although protein expression levels of Smad2, Smad4, Smad7, and Sp1 in the mesangial cells were similar in the two mouse strains, upregulation of p300 was marked in HIGA mice. Expression of p300 in renal tissues of HIGA mice was also enhanced in HIGA mice when compared with C57BL/6 mice. In HIGA mice, p300 expression was upregulated in the mesangial cells both in vitro and in vivo. It appears that the upregulation of p300 may be related to glomerular sclerosis associated with IgA nephropathy in HIGA mice.