Angiotensin II mediates LDL-induced superoxide generation in mesangial cells.
Lipid abnormalities and activation of the local renin-angiotensin system (RAS) may be involved in the pathogenesis of chronic glomerular disease. This study investigated whether low-density lipoprotein (LDL) activates local RAS in cultured human mesangial cells (HMC) and, at the same time, whether ANG II mediates LDL-induced mesangial cell proliferation, hypertrophy, and superoxide (O2-) generation. Quiescent HMC were exposed to 50 to 200 microg/ml of LDL or 10-7 to 10-10 M ANG II for 0.5 to 24 h in the presence or absence of 10-6 M losartan, an ANG II type I (AT1) receptor antagonist, or 10-5 M diphehylendieodonium (DPI) or 10-4 M apocynin, inhibitors of nicotinamide adenine dinucleotide phosphate oxidase. LDL induced an up to threefold increase in the ANG II levels in the culture medium of HMC. LDL upregulated AT1 receptor and angiotensinogen mRNA expression in HMC. LDL incubated with HMC increased O2- production by up to 3.3 times compared with the level of control cells. The LDL-induced, increased O2- generation was suppressed by losartan, DPI, or apocynin. LDL significantly increased mesangial [3H]thymidine or [3H]leucine incorporation, whereas these processes were abrogated by losartan. In conclusion, LDL increases ANG II production by mesangial cells, which in turn results in increased O2- production, and cell proliferation and hypertrophy, these effects of ANG II being mediated by the AT1 receptor.
Park
So Yeon
SY
Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, Korea.
Song
Chi Young
CY
Kim
Bong Cho
BC
Hong
Hye Kyoung
HK
Lee
Hyun Soon
HS
D000328:Adult; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006984:Hypertrophy; D008077:Lipoproteins, LDL / Q000494:pharmacology / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009861:Onium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D009861:Onium Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D019808:Losartan