Mesangial expression of angiotensin II receptor in IgA nephropathy and its regulation by polymeric IgA1.
BACKGROUND
Enhanced gene expression for the renin-angiotensin system (RAS) is detected in glomerular mesangial cells in IgA nephropathy (IgAN). Preliminary studies showed a reduced glomerular gene expression of angiotensin II subtype 1 receptor (AT1R), suggesting a regulatory response to high intrarenal angiotensin II (Ang II) concentration in IgAN.


METHODS
We examined the effect of polymeric IgA1 (pIgA1) from patients with IgAN on the expression of Ang II receptors in cultured human mesangial cells (HMC).


RESULTS
Polymeric IgA1 from patients with IgAN down-regulated the expression of AT1R in HMC in a dose-dependent manner. When similar experiments were conducted with addition of an angiotensin-converting enzyme inhibitor (captopril) or an AT1R antagonist (losartan), there was a significant increase in the expression of AT1R. Blockade of Ang II with captopril or losartan alone resulted in a stepwise increase of AT1R in cultured HMC. Down-regulation of Ang II subtype 2 receptor (AT2R) was not observed in HMC cultured with pIgA1 from patients with IgAN. The acute suppressive effect of pIgA1 from IgAN on the expression of AT1R was confirmed in HMC incubated with IgA isolated from 15 IgAN patients, 15 healthy subjects, and other glomerulonephritides control subjects. Reduced glomerular expression of AT1R (but not AT2R) was also demonstrated in renal biopsies from patients with IgAN.


CONCLUSIONS
Our findings demonstrate an altered AT1R expression in HMC in response to raised intrarenal Ang II in IgAN. Our in vitro studies also support that an imbalance of AT1R and AT2R activity in HMC following exposure to pIgA plays a significant pathogenetic role in the inflammatory injury in IgAN.
Lai
Kar Neng
KN
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong. knlai@hkucc.hku.hk
Chan
Loretta Y Y
LY
Tang
Sydney C W
SC
Tsang
Anita W L
AW
Li
Felix F K
FF
Lam
Man Fai
MF
Lui
Sing Leung
SL
Leung
Joseph C K
JC
D017209:Apoptosis / Q000502:physiology; D001706:Biopsy; D002478:Cells, Cultured; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D005922:Glomerulonephritis, IGA / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007070:Immunoglobulin A / Q000378:metabolism* / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology
D007070:Immunoglobulin A; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2