Genetic deletion of the angiotensin-(1-7) receptor Mas leads to glomerular hyperfiltration and microalbuminuria.
Angiotensin-(1-7), an active fragment of both angiotensins I and II, generally opposes the vascular and proliferative actions of angiotensin II. Here we evaluated effects of the angiotensin-(1-7) receptor Mas on renal physiology and morphology using Mas-knockout mice. Compared to the wild-type animals, Mas knockout mice had significant reductions in urine volume and fractional sodium excretion without any significant change in free-water clearance. A significantly higher inulin clearance and microalbuminuria concomitant with a reduced renal blood flow suggest that glomerular hyperfiltration occurs in the knockout mice. Histological analysis found reduced glomerular tuft diameter and increased expression of collagen IV and fibronectin in the both the mesangium and interstitium, along with increased collagen III in the interstitium. These fibrogenic changes and the renal dysfunction of the knockout mice were associated with an upregulation of angiotensin II AT1 receptor and transforming growth factor-beta mRNA. Our study suggests that Mas acts as a critical regulator of renal fibrogenesis by controlling effects transduced through angiotensin II AT1 receptors in the kidney.
Pinheiro
Sérgio V B
SVB
Pediatric Nephrology Unit, Medicine Faculty, Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Ferreira
Anderson J
AJ
Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Kitten
Gregory T
GT
Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
da Silveira
Kátia D
KD
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
da Silva
Deivid A
DA
Pediatric Nephrology Unit, Medicine Faculty, Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Santos
Sérgio H S
SHS
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Gava
Elisandra
E
Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Castro
Carlos H
CH
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Magalhães
Júnio A
JA
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
da Mota
Renata K
RK
Department of Morphology, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Botelho-Santos
Giancarla A
GA
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Bader
Michael
M
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Alenina
Natalia
N
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Santos
Robson A S
RAS
Department of Physiology and Biophysics, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Simoes E Silva
Ana Cristina
AC
Pediatric Nephrology Unit, Medicine Faculty, Department of Pediatrics, Federal University of Minas Gerais, Belo Horizonte, Brazil. Electronic address: acssilva@hotmail.com.
D000419:Albuminuria / Q000209:etiology* / Q000235:genetics; D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D017353:Gene Deletion; D005919:Glomerular Filtration Rate; D007678:Kidney Glomerulus / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics*; D015854:Up-Regulation
D005353:Fibronectins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D003094:Collagen