Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats

Abstract

The aim of this study was to evaluate the effect of compound 21 (C21), a selective AT 2 receptor agonist, on diabetic nephropathy and the potential additive effect of C21, when associated with losartan treatment, on the development of albuminuria and renal fibrosis in Zucker diabetic fatty (ZDF) rats. The experiments lasted 15 wk (from 5 to 20 wk of age) and were performed in 40 ZDF rats and 12 control lean rats. ZDF rats were divided into 4 groups: 1) 9 rats were treated with losartan; 2) 10 rats were treated with C21; 3) 9 rats were treated with losartan plus C21; and 4) 12 rats were maintained without any treatment. ZDF rats showed an increase in blood glucose level, albuminuria, renal fibrosis, macrophage infiltration, and TNF-␣ expression and a reduction of glomerular nephrin expression compared with control lean rats. C21 treatment reduced renal glomerular, tubulointerstitial, and perivascular fibrosis, and macrophage infiltration and TNF-␣ expression in ZDF rats. C21 treatment caused a decrease in albuminuria in ZDF rats up to 11 wk of age. Losartan decreased macrophage infiltration, TNF-␣ expression, and renal glomerular and perivascular fibrosis, restored glomerular nephrin expression, but did not affect tubulointerstitial fibrosis. Losartan treatment caused a decrease in albuminuria in ZDF rats up to 15 wk of age. At the end of the protocol, only the combination of C21 plus losartan significantly reduced albuminuria in ZDF rats. These data demonstrate that C21 has beneficial effects on diabetic nephropathy, suggesting the combination of C21 and losartan as a novel pharmacological tool to slow the progression of nephropathy in type II diabetes. diabetic nephropathy; compound 21; urinary albumin excretion; experimental models; renal fibrosis; Zucker diabetic fatty rats DIABETIC NEPHROPATHY IS STILL the worldwide leading cause of end-stage renal disease (2,26,35). In the case of diabetes, hyperglycemia is undoubtedly the determining cause for the development of nephropathy, but often in diabetic patients concomitant factors, such as high blood pressure, dyslipidemia, and the presence of albuminuria, accelerate the progression of renal disease. Consequently, in addition to a tight correction of blood glucose levels, a careful control of blood pressure, dyslipidemia, and albuminuria are essential to slow down the progression of nephropathy (3,32,33).Angiotensin II, the main effector of the renin-angiotensin system, plays a key role in the progression of diabetic nephropathy. Accordingly, drugs acting on the renin-angiotensin system, by inhibiting angiotensin-converting enzyme or by blocking angiotensin II type 1 (AT 1 ) receptors, are the treatment of choice for diabetic nephropathy. Angiotensin II binds to two G protein-coupled receptors, the AT 1 and the angiotensin II type 2 (AT 2 ) receptors. The well-known hemodynamic (i.e., vasoconstriction) or cellular effects (i.e., profibrotic and proinflammatory effects) of angiotensin II are mediated by AT 1 receptors, while the stimulation of AT 2 receptors coun...

AT2R deficiency mediated podocyte loss via activation of ectopic hedgehog interacting protein (Hhip) gene expression

“…Together, these data suggested that the lack of AT 2 R might not interrupt the sequence of the final nephron formation, but instead modify the maturation, integrity, and function of specialized renal cells, such as podocytes. In line with the observations that AT 2 R enhanced the expression of slit diaphragm molecules [40] and AT 2 R had a renoprotective effect to prevent diabetic nephropathy occurring in Zucker rats [41], we found that several podocyte markers, such as p57, WT-1, nephrin, and Synpo expression, were significantly decreased in the glomeruli of AT 2 RKO mice at 3 weeks of age that had a detectable amount of albumin leakage in their urine. Together, these data underscore the functional role of AT 2 R in podocyte formation and integrity.…”

RAS and sex differences in diabetic nephropathy

“…In concordance, C21 improved albuminuria through the prevention of renal inflammation and production of NO and cGMP in STZ-induced male SpragueDawley rats (73). In T2DM, C21 treatment in combination with losartan showed an additive effect on reducing albuminuria and slowing the progression of nephropathy in male Zucker diabetic fatty rats (14). Acute C21 administration improved renal function in female, but not in male, spontaneously hypertensive (SHR) rats.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…AT 2 R also has anti-inflammatory and antioxidative functions in the kidney in obese Zucker rats but proinflammatory and pro-oxidative functions in lean Zucker rats (895). An AT 2 R agonist may also prevent diabetic nephropathy through a similar mechanism (130,513). However, there are certain limitations in these studies such as specificity issues of pharmacological AT 2 R agonists/antagonists and the AT 2 R antibody utilized.…”