Accelerated fibrosis and collagen deposition develop in the renal interstitium of angiotensin type 2 receptor null mutant mice during ureteral obstruction.
We examined the role of angiotensin in renal remodeling that is specifically channeled through the angiotensin type 2 receptor (AT2 receptor). Previously, we observed that in mouse embryonic kidneys the AT2 mRNA is predominantly expressed in the mesenchyme. We therefore chose a model of unilateral ureteral obstruction, characterized by activation of the renin-angiotensin system, while fibrosis develops prominently within the renal interstitium. Male wild-type mice (Agtr2 -/Y) and mice null mutant for the AT2 gene (Agtr2 -/Y) were subjected to a complete unilateral ureteral ligation for 5 or 14 days. Obstructed kidneys of Agtr2 -/Y mice showed more severe interstitial fibrosis than those of Agtr2 +/Y mice, confirmed by increased collagen by point-counting on Masson trichrome stained sections, and increased alpha 1(I) collagen mRNA expression by Northern blot. Immunohistochemistry staining for PCNA (a marker of cell proliferation), F4/80 (a marker of macrophages), vimentin (a marker of fibroblasts), and alpha SMA (a marker of myofibroblasts) revealed that, while the two groups were comparable in the degree of cell proliferation and macrophage infiltration, fibroblasts/ myofibroblasts were present in a greater abundance in obstructed kidneys of Agtr2 -/Y mice than in Agtr2 +/Y at both 5 and 14 days after obstruction. Moreover, cells undergoing apoptosis were significantly less in Agtr2 -/Y than in Agtr2 +/Y. Thus, the AT2 receptor significantly impacts the remodeling process within renal interstitium, potentially by regulating the population of collagen-producing cells.
Ma
J
J
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nishimura
H
H
Fogo
A
A
Kon
V
V
Inagami
T
T
Ichikawa
I
I
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003094:Collagen / Q000032:analysis*; D005355:Fibrosis; D015870:Gene Expression; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology*
D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D003094:Collagen