TY - JOUR
T1 - Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice
AU - Ichihara, Atsuhiro
AU - Sakoda, Mariyo
AU - Kurauchi-Mito, Asako
AU - Nishiyama, Akira
AU - Itoh, Hiroshi
N1 - Funding Information:
This work was supported in part by Grants from the Ministry of Education, Culture, Sports, Science and Technology (17390249), from the Takeda Science Foundation, and from the Japan Diabetes Foundation.
PY - 2008/9
Y1 - 2008/9
N2 - Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.
AB - Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.
KW - Albuminuria
KW - angiotensin
KW - glomerulosclerosis
KW - type 2 diabetes
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U2 - 10.1016/j.jash.2008.04.009
DO - 10.1016/j.jash.2008.04.009
M3 - Article
C2 - 20409915
AN - SCOPUS:51449113656
SN - 1933-1711
VL - 2
SP - 332
EP - 340
JO - Journal of the American Society of Hypertension
JF - Journal of the American Society of Hypertension
IS - 5
ER -
