Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides.

Abstract

BACKGROUND AND AIM:

The infusion of chronic angiotensin II (Ang II) has been shown to promote renal interstitial fibrosis. To evaluate the pathophysiological significance of the natriuretic peptide-GC-A system, we infused Ang II (1.0 mg/kg/day) in GC-A-deficient mice (GC-A-KO).

METHODS:

We used 5 groups (Wild-Saline n = 12, Wild-Ang II n = 14, GC-A-KO-Saline n = 11, GC-A-KO-Ang II n = 13, and GC-A-KO-Ang II-Hydralazine n = 10). Saline or Ang II was infused subcutaneously using an osmotic minipump for 3 weeks. Hydralazine was administered orally (0.05 g/L in drinking water).

RESULTS:

Systolic blood pressure was significantly higher in the GC-A-KO-Saline group (130 ± 12 mmHg) than in the Wild-Saline group (105 ± 30 mmHg), and was similar to that in the Wild-Ang II (141 ± 17 mmHg) and GC-A-KO-Ang II-Hydralazine (140 ± 20 mmHg) groups. Systolic blood pressure was significantly higher in the GC-A-KO-Ang II group (159 ± 21 mmHg) than in the 4 other groups. Renal tubular atrophy and interstitial fibrosis were significantly more severe in the GC-A-KO-Ang II group (atrophy 13.4 %, fibrosis 12.0 %) than in the Wild-Saline (0, 2.0 %), Wild-Ang II (2.9, 4.4 %), and GC-A-KO-Saline (0, 2.6 %) groups. Hydralazine could not inhibit this aggravation (GC-A-KO-Ang II-Hydralazine 13.5, 11.3 %). The expression of monocyte chemotactic protein-1 in tubular cells, and F4/80 and alpha-smooth muscle actin in the interstitium was clearly detected in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy and interstitial fibrosis. The expression of E-cadherin in tubular cells was absent in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy.

CONCLUSIONS:

The natriuretic peptide-GC-A system may play an inhibitory role in Ang II-induced renal tubular atrophy, interstitial fibrosis, and phenotypic transformation in renal tubular cells and fibroblasts.

• Authors: Fumiki Yoshihara, Takeshi Tokudome, Ichiro Kishimoto, Kentaro Otani, Atsunori Kuwabara, Takeshi Horio, Yuhei Kawano, Kenji Kangawa
• Journal: Clinical and experimental nephrology (Clin Exp Nephrol) Vol. 19 Issue 2 Pg. 197-207 (Apr 2015) ISSN: 1437-7799 [Electronic] Japan
• PMID: 24845230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Antigens, Differentiation
• Antihypertensive Agents
• Cadherins
• Chemokine CCL2
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• NPHS2 protein
• RNA, Messenger
• Vasoconstrictor Agents
• alpha-smooth muscle actin, mouse
• monocyte-macrophage differentiation antigen
• Osteopontin
• Angiotensin II
• Hydralazine
• Sodium Chloride
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Actins (analysis)
• Angiotensin II (pharmacology)
• Animals
• Antigens, Differentiation (analysis, genetics)
• Antihypertensive Agents (pharmacology)
• Atrophy
• Blood Pressure (drug effects, genetics)
• Cadherins (analysis)
• Chemokine CCL2 (analysis)
• Fibrosis
• Gene Expression (drug effects)
• Hydralazine (pharmacology)
• Intracellular Signaling Peptides and Proteins (genetics)
• Kidney Tubules (chemistry, pathology)
• Male
• Membrane Proteins (genetics)
• Mice
• Mice, Knockout
• Osteopontin (genetics)
• RNA, Messenger (metabolism)
• Receptors, Atrial Natriuretic Factor (deficiency, genetics)
• Sodium Chloride (pharmacology)
• Vasoconstrictor Agents (pharmacology)