Targeted disruption of guanylyl cyclase-A/natriuretic peptide receptor-A gene provokes renal fibrosis and remodeling in null mutant mice: role of proinflammatory cytokines.

Abstract

Binding of atrial and brain natriuretic peptides to guanylyl cyclase-A/natriuretic peptide receptor-A produces second messenger cGMP, which plays an important role in maintaining renal and cardiovascular homeostasis. Mice carrying a targeted disruption of the Npr1 gene coding for guanylyl cyclase-A/natriuretic peptide receptor-A exhibit changes that are similar to those that occur in untreated human hypertension, including elevated blood pressure, cardiac hypertrophy, and congestive heart failure. The objective of this study was to determine whether disruption of the Npr1 gene in mice provokes kidney fibrosis, remodeling, and derangement. We found that systemic disruption of the Npr1 gene causes increased renal tubular damage characterized by dilation, flattening of epithelium, and expansion of interstitial spaces in Npr1(-/-) (0-copy) mice. Significant increases occurred in the expression levels of TNF-α (4-fold), IL-6 (4.5-fold), and TGF-β1 (2-fold) in 0-copy null mutant mice compared with 2-copy wild-type mice. An increased epithelial-to-mesenchymal transition indicated by increased expression of α-smooth muscle actin, was observed in Npr1(-/-) mouse kidneys. Treatment with captopril and losartan showed a 38 and 46% attenuation in fibrosis and 30 and 42% reduction in α-smooth muscle actin immunoexpression, respectively, in 1-copy and 0-copy mice compared with 2-copy mice. Although bendroflumethiazide treatment did not show any effect. The present results demonstrate that the disruption of Npr1 gene activates proinflammatory cytokines leading to fibrosis, hypertrophic growth, and remodeling of the kidneys of mutant mice.

• Authors: Subhankar Das, Edward Au, Stephen T Krazit, Kailash N Pandey
• Journal: Endocrinology (Endocrinology) Vol. 151 Issue 12 Pg. 5841-50 (Dec 2010) ISSN: 1945-7170 [Electronic] United States
• PMID: 20881240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antihypertensive Agents
• Cytokines
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Antihypertensive Agents (pharmacology)
• Blood Pressure
• Cytokines (genetics, metabolism)
• Fibrosis (genetics, metabolism)
• Gene Expression Regulation (physiology)
• Hypertension (drug therapy)
• Hypertrophy (genetics, metabolism)
• Kidney Diseases (genetics, metabolism)
• Mice
• Mice, Knockout
• Receptors, Atrial Natriuretic Factor (metabolism)