Natriuretic peptide receptor guanylyl cyclase-A protects podocytes from aldosterone-induced glomerular injury.
Natriuretic peptides produced by the heart in response to cardiac overload exert cardioprotective and renoprotective effects by eliciting natriuresis, reducing BP, and inhibiting cell proliferation and fibrosis. These peptides also antagonize the renin-angiotensin-aldosterone system, but whether this mechanism contributes to their renoprotective effect is unknown. Here, we examined the kidneys of mice lacking the guanylyl cyclase-A (GC-A) receptor for natriuretic peptides under conditions of high aldosterone and high dietary salt. After 4 weeks of administering aldosterone and a high-salt diet, GC-A knockout mice, but not wild-type mice, exhibited accelerated hypertension with massive proteinuria. Aldosterone-infused GC-A knockout mice had marked mesangial expansion, segmental sclerosis, severe podocyte injury, and increased oxidative stress. Reducing the BP with hydralazine failed to lessen such changes; in contrast, blockade of the renin-angiotensin-aldosterone system markedly reduced albuminuria, ameliorated podocyte injury, and reduced oxidative stress. Furthermore, treatment with the antioxidant tempol significantly reduced albuminuria and abrogated the histologic changes. In cultured podocytes, natriuretic peptides inhibited aldosterone-induced mitogen-activated protein kinase phosphorylation. Taken together, these results suggest that renoprotective properties of the endogenous natriuretic peptide/GC-A system may result from the local inhibition of the renin-angiotensin-aldosterone system and oxidative stress in podocytes.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
Yoshihisa
Y
Ogawa
Masashi
M
Mukoyama
Hideki
H
Yokoi
Masato
M
Kasahara
Kiyoshi
K
Mori
Yukiko
Y
Kato
Takashige
T
Kuwabara
Hirotaka
H
Imamaki
Tomoko
T
Kawanishi
Kenichi
K
Koga
Akira
A
Ishii
Takeshi
T
Tokudome
Ichiro
I
Kishimoto
Akira
A
Sugawara
Kazuwa
K
Nakao
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology* / Q000517:prevention & control; D000450:Aldosterone / Q000009:adverse effects* / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006830:Hydralazine / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000139:chemically induced / Q000473:pathology; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000009:adverse effects / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000959:Antihypertensive Agents; D017673:Sodium Chloride, Dietary; D006830:Hydralazine; D000450:Aldosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A