Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides.
OBJECTIVE
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.
Division of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan, fyoshi@hsp.ncvc.go.jp.
Fumiki
F
Yoshihara
Takeshi
T
Tokudome
Ichiro
I
Kishimoto
Kentaro
K
Otani
Atsunori
A
Kuwabara
Takeshi
T
Horio
Yuhei
Y
Kawano
Kenji
K
Kangawa
D000199:Actins / Q000032:analysis; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis / Q000235:genetics; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001284:Atrophy; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D015820:Cadherins / Q000032:analysis; D018932:Chemokine CCL2 / Q000032:analysis; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006830:Hydralazine / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000172:deficiency* / Q000235:genetics; D012965:Sodium Chloride / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000199:Actins; D000943:Antigens, Differentiation; D000959:Antihypertensive Agents; D015820:Cadherins; D018932:Chemokine CCL2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; C544013:alpha-smooth muscle actin, mouse; C036763:monocyte-macrophage differentiation antigen; D053495:Osteopontin; D000804:Angiotensin II; D006830:Hydralazine; D012965:Sodium Chloride; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A