HO-1 induction ameliorates experimental murine membranous nephropathy: anti-oxidative, anti-apoptotic and immunomodulatory effects.
BACKGROUND
Therapeutic agents for membranous nephropathy (MN) remain ill-defined. Haeme oxygenase (HO)-1 is considered to play a protective role in various disorders. Here, we assessed the efficacy of HO-1 induction therapy for MN.


METHODS
MN was induced in BALB/c mice with intravenous injections of cationic bovine serum albumin. Three groups of mice were administered 100 micromol/kg Cobalt protoporphyrin (CoPP, a potent HO-1 inducer), Tin protoporphyrin (SnPP, a potent HO-1 inhibitor) or phosphate-buffered saline via intra-peritoneal injections once a week starting from the induction of MN. Disease severity was verified by serum and urine metabolic profiles and by renal histopathology. Cytokine profiles, immunoglobulin production, the expression of oxidative stress markers (thiobarbituric acid reactive substances, TBARS) and apoptosis, as measured by TUNEL, were also determined.


RESULTS
Mice treated with CoPP displayed a significant reduction in proteinuria and a marked amelioration of glomerular lesions, accompanied by attenuated immune-complex deposition. The production of immunoglobulins in MN mice treated with CoPP was significantly reduced compared with that of mice in the other two groups. TBARS in the serum and kidneys, as well as apoptosis, were also significantly reduced in CoPP-treated mice. Cytokine mRNA expression in the renal cortex indicated that CoPP not only decreased the expression of proinflammatory cytokines, but also increased the expression of anti-inflammatory cytokines (interleukin-10).


CONCLUSIONS
HO-1 induction therapy may ameliorate experimental MN via multiple pathways, including anti-oxidative, anti-apoptotic and immunomodulatory effects. HO-1 inducing regimens should be considered as a potential therapeutic intervention in MN in the future.
Wu
Chia-Chao
CC
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Nei-Hu, Taipei 114, Taiwan.
Lu
Kuo-Cheng
KC
Chen
Jin-Shuen
JS
Hsieh
Hsin-Yi
HY
Lin
Shih-Hua
SH
Chu
Pauling
P
Wang
Jia-Yi
JY
Sytwu
Huey-Kang
HK
Lin
Yuh-Feng
YF
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007136:Immunoglobulins / Q000097:blood; D007155:Immunologic Factors / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D017931:DNA Primers; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D007155:Immunologic Factors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; C007095:cobaltiprotoporphyrin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1