Polymeric IgA1 from patients with IgA nephropathy upregulates transforming growth factor-beta synthesis and signal transduction in human mesangial cells via the renin-angiotensin system.
The effects of polymeric IgA1 (pIgA1) and monomeric IgA1 (mIgA1) from patients with IgA nephropathy (IgAN) on the renin-angiotensin system (RAS) and TGF-beta synthesis were examined in cultured human mesangial cells (HMC). Both pIgA1 and mIgA1 induced renin gene expression in HMC, in a dose-dependent manner. Similar findings were observed for TGF-beta gene and protein expression. The values measured in HMC incubated with pIgA1 were significantly higher than those in HMC incubated with equivalent amounts of mIgA1. When similar experiments were performed with the addition of either captopril or losartan, there was a significant increase in the renin gene expression by HMC, whereas the synthesis of TGF-beta was markedly reduced. The TGF-beta signal transduction pathways in HMC were studied by measuring the receptor-regulated Smad proteins (Smad 2 and 3) and common-partner Smad proteins (Smad 4). pIgA1 from patients with IgAN upregulated Smad activity in HMC, and the activity observed in HMC that had been preincubated with pIgA1 was readily suppressed with optimal concentrations of captopril or losartan. The effects of pIgA1 on the RAS were further examined in HMC incubated with IgA isolated from 30 patients with IgAN, 30 healthy subjects, and disease control subjects with other diseases. pIgA1 induction of angiotensin II or TGF-beta synthesis in HMC was significantly greater with preparations from patients with IgAN, compared with healthy or disease control subjects. The findings support a pathogenetic role of pIgA1 in IgAN through upregulation of the RAS and TGF-beta, leading to chronic renal failure with renal fibrosis.
Lai
Kar Neng
KN
Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong. knlai@hkucc.hku.hk
Tang
Sydney C W
SC
Guh
Jinn-Yuh
JY
Chuang
Tsai-Der
TD
Lam
Man Fai
MF
Chan
Loretta Y Y
LY
Tsang
Anita W L
AW
Leung
Joseph C K
JC
D002216:Captopril / Q000008:administration & dosage; D002478:Cells, Cultured; D011905:Genes, ras / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology*; D005922:Glomerulonephritis, IGA; D006801:Humans; D007070:Immunoglobulin A; D019808:Losartan / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis; D012083:Renin / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation
D007070:Immunoglobulin A; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D002216:Captopril; D012083:Renin; D019808:Losartan