Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury.
One of major causes of end-stage renal disease is glomerulonephritis, the treatment of which remains difficult clinically. It has already been shown that transgenic mice that overexpress brain natriuretic peptide (BNP), with a potent vasorelaxing and natriuretic property, have ameliorated glomerular injury after subtotal nephrectomy. However, the role of natriuretic peptides in immune-mediated renal injury still remains unknown. Therefore, the effects of chronic excess of BNP on anti-glomerular basement membrane nephritis induced in BNP-transgenic mice (BNP-Tg) were investigated and the mechanisms how natriuretic peptides act on mesangial cells in vitro were explored. After induction of nephritis, severe albuminuria (approximately 21-fold above baseline), tissue damage, including mesangial expansion and cell proliferation, and functional deterioration developed in nontransgenic littermates. In contrast, BNP-Tg exhibited much milder albuminuria (approximately fourfold above baseline), observed only at the initial phase, and with markedly ameliorated histologic and functional changes. Up-regulation of transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1), as well as increased phosphorylation of extracellular signal-regulated kinase (ERK), were also significantly inhibited in the kidney of BNP-Tg. In cultured mesangial cells, natriuretic peptides counteracted the effects of angiotensin II with regard to ERK phosphorylation and fibrotic action. Because angiotensin II has been shown to play a pivotal role in the progression of nephritis through induction of TGF-beta and MCP-1 that may be ERK-dependent, the protective effects of BNP are likely to be exerted, at least partly, by antagonizing the renin-angiotensin system locally. The present study opens a possibility of a novel therapeutic potential of natriuretic peptides for treating immune-mediated renal injury.
Suganami
Takayoshi
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mukoyama
Masashi
M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Sugawara
Akira
A
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Mori
Kiyoshi
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nagae
Tetsuya
T
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kasahara
Masato
M
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yahata
Kensei
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Makino
Hisashi
H
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Fujinaga
Yuriko
Y
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Ogawa
Yoshihiro
Y
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Tanaka
Issei
I
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Nakao
Kazuwa
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
D000419:Albuminuria / Q000652:urine; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D045283:Natriuretic Agents / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D011921:Rats, Inbred WKY; D012709:Serum Albumin / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D000959:Antihypertensive Agents; D018932:Chemokine CCL2; D003176:Complement C3; D007074:Immunoglobulin G; D045283:Natriuretic Agents; D012709:Serum Albumin; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D020097:Natriuretic Peptide, Brain; D006830:Hydralazine; D020928:Mitogen-Activated Protein Kinases