Temporary Angiotensin II Blockade at the Prediabetic Stage Attenuates the Development of Renal Injury in Type 2 Diabetic Rats

Abstract

Whether temporary angiotensin II (AngII) blockade at the prediabetic stage attenuates renal injury in type 2 diabetic OLETF rats later in life was investigated. OLETF rats were treated with an AT 1 receptor antagonist (olmesartan, 0.01% in food), angiotensin-converting enzyme inhibitor (temocapril, 0.01% in food), a combination of the two, or hydralazine (25 mg/kg per d) at the prediabetic stage (4 to 11 wk of age) and then monitored without further treatment until 50 wk of age. At 11 wk of age, blood glucose levels and urinary protein excretion (U protein V) were similar between OLETF and control LETO rats. However, OLETF rats showed higher kidney AngII contents and type IV collagen mRNA expression than LETO rats at this age. These decreased with olmesartan, temocapril, and a combination of these but not with hydralazine. At 50 wk of age, diabetic OLETF rats showed higher BP, U protein V, and intrarenal AngII levels than LETO rats. Temporary AngII blockade did not affect glucose metabolism or the development of hypertension in OLETF rats but significantly suppressed proteinuria and ameliorated glomerular injury. However, no parameters were affected by temporary hydralazine treatment. The present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes becomes apparent in OLETF rats. Furthermore, temporary AngII blockade at the prediabetic stage attenuates the progression of renal injury in these animals. These data suggest that early AngII blockade could be an effective strategy for preventing the development of type 2 diabetic renal injury later in life. D iabetic nephropathy is a major complication in diabetes and a leading cause of end-stage renal failure, which causes disabilities and a high mortality rate in patients with this disease (1). The mechanisms underlying the development of diabetic nephropathy are extremely complex; however, the potential role of the renin-angiotensin system (RAS) has been suggested (2-13). Recent studies indicate that in diabetes, intrarenal generation of angiotensin II (AngII) is elevated despite suppressed circulating RAS (5,6). Furthermore, AT 1 receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEI) have been shown to attenuate the progression of diabetic nephropathy (3,4,7-13). Several clinical trials have shown that ARB are more effective than traditional antihypertensive therapies in reducing renal failure progression in patients with type 2 diabetes and that the renoprotective effects of ARB are independent of their antihypertensive actions (8 -11). Of interest, it has also been shown that ACEI treatment of normotensive patients with diabetes and little or no proteinuria (early stages of diabetic nephropathy) results in long-term stabilization of plasma creatinine levels and urinary protein excretion rates (U protein V) (12,13). These observations suggest that angiotensin blockade has clinical benefits for patients who have diabetes and have no or early signals of renal disease.It has been sho...

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

“…12,38 Previous reports of activated local RAS with an increased local production of Ang II and an expression of AT1 receptor in experimental rats modeling hypertension, diabetes mellitus and subtotal nephrectomy support this assertion. [41][42][43] Taken together, these results suggest that ARBs exhibit renoprotective effects by blocking local RAS in the kidney.…”

Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury

“…The severity of glomerular proliferation, interstitial fibrosis, and tubular proteinaceous cast scores were evaluated using light microscopy according to previously described methods (4,25,(33)(34)(35)(36)(37). Briefly, glomerular proliferative lesions were scored into five grades as follows: 0, no proliferation; 1, minor (segmental lesion Ͻ25%); 2, mild (segmental lesion Ͼ25% but Ͻ50%); 3, moderate (diffuse proliferation without severe sclerotic change); and 4, severe (diffuse proliferation with nearly complete sclerosis) (4,33,34,36). A minimum of 40 glomeruli were examined in each PAS-stained specimen.…”

“…␤ 1 , CTGF, and monocyte chemoattractant protein-1 (MCP-1) were analyzed by real-time PCR using an ABI Prism 7000 Sequence Detection System (Applied Biosystems, Foster City, CA) (17,33,34). The oligonucleotide primer sequences of GAPDH and types I and III collagen were reported previously (17,33).…”

“…The oligonucleotide primer sequences of GAPDH and types I and III collagen were reported previously (17,33). TGF-␤ 1 , CTGF, and MCP-1 mRNA expression were measured using TaqMan Gene Expression Assay kits (Applied Biosystems) (33,34).…”

Diabetic Glomerulopathy

“…Blockade of the renin-angiotensin-aldosterone system antagonizes the profibrotic effects of angiotensin II by reducing its stimulation of TGF-1 (Hilker, KF, 2005). Support that such profibrotic effects underlie diabetic nephropathy has also been provided by study of an animal model of diabetic nephropathy (Nagai Y, 2005). Transient blockade of the renin-angiotensin system (for 7 weeks) in prediabetic rats reduced proteinuria and improved glomerular structure.…”