H(2)S inhibits hyperglycemia-induced intrarenal renin-angiotensin system activation via attenuation of reactive oxygen species generation.
Decrease in endogenous hydrogen sulfide (H2S) was reported to participate in the pathogenesis of diabetic nephropathy (DN). This study is aimed at exploring the relationship between the abnormalities in H2S metabolism, hyperglycemia-induced oxidative stress and the activation of intrarenal renin-angiotensin system (RAS). Cultured renal mesangial cells (MCs) and streptozotocin (STZ) induced diabetic rats were used for the studies. The expressions of angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin II (Ang II) type I receptor (AT1), transforming growth factor-β1 (TGF-β1) and collagen IV were measured by real time PCR and Western blot. Reactive oxygen species (ROS) production was assessed by fluorescent probe assays. Cell proliferation was analyzed by 5'-bromo-2'-deoxyuridine incorporation assay. Ang II concentration was measured by an enzyme immunoassay. AGT, ACE and AT1 receptor mRNA levels and Ang II concentration were increased in high glucose (HG) -treated MCs, the cell proliferation rate and the production of TGF-β1 and of collagen IV productions were also increased. The NADPH oxidase inhibitor diphenylenechloride iodonium (DPI) was able to reverse the HG-induced RAS activation and the changes in cell proliferation and collagen synthesis. Supplementation of H2S attenuated HG-induced elevations in ROS and RAS activation. Blockade on H2S biosynthesis from cystathione-γ-lyase (CSE) by DL-propargylglycine (PPG) resulted in effects similar to that of HG treatment. In STZ-induced diabetic rats, the changes in RAS were also reversed by H2S supplementation without affecting blood glucose concentration. These data suggested that the decrease in H2S under hyperglycemic condition leads to an imbalance between oxidative and reductive species. The increased oxidative species results in intrarenal RAS activation, which, in turn, contributes to the pathogenesis of renal dysfunction.
Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.
Hong
H
Xue
Ping
P
Yuan
Jun
J
Ni
Chen
C
Li
Decui
D
Shao
Jia
J
Liu
Yang
Y
Shen
Zhen
Z
Wang
Li
L
Zhou
Wei
W
Zhang
Yu
Y
Huang
Chen
C
Yu
Rui
R
Wang
Limin
L
Lu
D000098:Acetophenones / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000098:Acetophenones; D047228:Angiotensin II Type 1 Receptor Blockers; D001786:Blood Glucose; D024141:Collagen Type IV; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; C007517:diphenyleneiodonium; C056165:acetovanillone; D019255:NADPH Oxidases; D007703:Peptidyl-Dipeptidase A; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D005947:Glucose; D019808:Losartan; D006862:Hydrogen Sulfide