Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice

• Published in: Journal of the American Society of Hypertension Vol. 2; no. 5; pp. 332 - 340
• Main Authors: Ichihara, Atsuhiro, MD, PhD, FAHA, Sakoda, Mariyo, MD, Kurauchi-Mito, Asako, MD, Nishiyama, Akira, MD, PhD, FAHA, Itoh, Hiroshi, MD, PhD
• Format: Journal Article
• Language: English
• Published: United States 01.09.2008
• Subjects: Cardiovascular; angiotensin; type 2 diabetes; Albuminuria; glomerulosclerosis
• ISSN: 1933-1711
• DOI: 10.1016/j.jash.2008.04.009

Abstract 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.