The Urotensin-II Receptor Antagonist Palosuran Improves Pancreatic and Renal Function in Diabetic Rats

Abstract

Urotensin-II (U-II) is a cyclic peptide that acts through a specific G-protein-coupled receptor, UT receptor. Urotensin-II and UT receptors have been described in pancreas and kidney, but their function is not well understood. We studied the effects of chronic treatment of diabetic rats with the orally active selective U-II receptor antagonist palosuran. Streptozotocin treatment causes pancreatic ␤-cell destruction and leads to the development of hyperglycemia, dyslipidemia, and renal dysfunction. Long-term treatment of streptozotocin-induced diabetic rats with palosuran improved survival, increased insulin, and slowed the increase in glycemia, glycosylated hemoglobin, and serum lipids. Furthermore, palosuran increased renal blood flow and delayed the development of proteinuria and renal damage. The U-II system is unique in that it plays a role both in insulin secretion and in the renal complications of diabetes. Urotensin receptor antagonism might be a new therapeutic approach for the treatment of diabetes.

Urotensin II receptor antagonism confers vasoprotective effects in diabetes associated atherosclerosis: studies in humans and in a mouse model of diabetes

“…We did, however, detect a small decrease in triacylglycerol levels in SB-657510-treated diabetic (but not non-diabetic control) Apoe KO mice. This is consistent with a previous report, which indicated that another UT antagonist, palosuran, significantly decreased serum triacylglycerol in diabetic rats [14]. We also found that SB-657510 treatment did not significantly change the expression of various genes encoding lipid scavenger receptors and regulators in the aorta of Apoe KO mice, despite a previous report of altered acetyl-CoA acetyltransferase 1 (ACAT-1) levels in the aorta of high-fat-fed Apoe KO mice treated with SB-657510 [11].…”

“…Additionally, chronic UII infusion has been shown to enhance macrophage foam cell formation [12] and atherosclerosis in high-fat-fed Apoe knockout (KO) mice [13]. While UT antagonism has been investigated in diabetic nephropathy [14,15], little is known of the role of UII in the development of diabetes-associated atherosclerosis.…”

Role of urotensin II in health and disease

“…When infused intravenously at a dose of 10 mg/(kg·h), palosuran provided protection to a rat model of renal ischemia-reperfusion via improved renal blood flow and significantly decreased tubulointerstitial lesions (25). When administered orally, palosuran improved renal function and increased survival, increased insulin levels, and slowed the increase in glycemia in a rat model of type I diabetes (26). Palosuran was also shown to reduce portal pressure, increase splanchnic vascular resistance, and decrease the portal inflow in a rat model of cirrhosis and in bile duct-ligated rats (131).…”

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…As a matter of fact, treatment of streptozotocin-induced diabetic rats with palosuran (Clozel et al, 2004) improves survival, increases serum insulin concentration, reduces glycemia, attenuates albuminuria, and prevents renal tubular degeneration (Clozel et al, 2006). However, clinical trials led to divergent results (Desai et al, 2008;Tsoukas et al, 2011).…”