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...

It has recently been shown that glomerular mesangial injury is associated with increases in renal cortical reactive oxygen species (ROS) levels in rats treated chronically with aldosterone and salt. This study was conducted to determine the mechanisms responsible for aldosterone-induced ROS production in cultured rat mesangial cells (RMC). Oxidative fluorescent dihydroethidium was used to evaluate intracellular production of superoxide anion (O 2 ؊ ) in intact cells. The lucigeninderived chemiluminescence assay was used to determine NADPH oxidase activity. The staining of dihydroethidium was increased in a dose-dependent manner by aldosterone (1 to 100 nmol/L) with a peak at 3 h in RMC. Aldosterone A growing body of evidence supports a role for aldosterone in the progression of renal injury (1-4). In rats, chronic administrations of aldosterone and salt led to severe proteinuria and glomerular injury (5,6). Similarly, exogenous infusion of aldosterone reversed the renoprotective effects of angiotensin-converting enzyme (ACE) inhibitors in remnant kidney hypertensive rats (7) and stroke-prone, spontaneously hypertensive rats (SHRSP) (8). In addition, treatment with the mineralocorticoid receptor (MR) antagonists ameliorated glomerular injury in SHRSP (9) and in rats treated with angiotensin II (AngII) and nitric oxide synthase inhibitor (10), cyclosporine A (11) or radiation (12), independent of BP reduction. In patients with chronic renal failure (13) and early diabetic nephropathy (14), addition of a nonselective MR antagonist, spironolactone, to ACE inhibitors did not exert hemodynamic effects, but markedly reduced urinary excretion rate of protein (U protein V). These observations suggest that aldosterone has direct deleterious effects on the kidney via activation of the MR. However, the mechanisms responsible for the aldosterone/MR-induced renal injury remain undetermined.Recent studies have indicated the potential participation of reactive oxygen species (ROS) in the pathophysiology of aldosterone-induced cardiovascular tissue injury (5,(15)(16)(17)(18)(19)(20)(21)(22). In aldosterone/salt-treated hypertensive rats, vascular NADPH oxidase activity and ROS production were markedly increased (15,16). In these animals, treatment with an NADPH oxidase inhibitor, apocynin, prevented BP elevation and cardiovascular hypertrophy (17). It was also shown that treatment with a selective MR antagonist, eplerenone, improved endothelial dysfunction and reduced vascular superoxide anion (O 2 Ϫ ) generation in diet-induced atherosclerosis (18). Similarly, eplerenone reduced aortic atherosclerotic lesions and O 2 Ϫ generation in peritoneal macrophages of apolipoprotein E-deficient mice (19,20). Mazak et al. (21) showed that aldosterone potentiates AngII-induced signaling in vascular smooth muscle cells, and that these effects of aldosterone were blocked by antioxidants. The authors also showed that spironolactone decreased NADPH

Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype-related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal alpha-actin, beta-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular alpha-myosin heavy chain and smooth muscle alpha-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-beta 1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II-induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract. Although liposome-encapsulated clodronate has been used as a means to deplete macrophages from certain tissues, target leukocyte subtypes within the kidney are not clearly known under normal and pathologic conditions. The present study was therefore conducted to examine the effects of liposome clodronate on renal infiltrating cell type following unilateral ureteral obstruction (UUO) and tried to correlate these changes to the mechanisms of early development of renal fibrosis. Renal infiltrating leukocyte subtypes and counts were determined by using multicolor flow cytometric analysis of cell suspensions from obstructed kidneys. UUO for 5 days elicited renal tubular apoptosis and renal fibrosis and showed 4-fold increase in renal leukocytes including monocytes/macrophages, dendritic cells, and T-cells. Repeated administration of liposome clodronate selectively depleted F4/80 + monocytes /macrophages and F4/80 + dendritic cells but not F4/80 − dendritic cells or other cell types in both obstructed and nonobstructed kidneys. Tubular apoptosis and renal fibrosis were also significantly attenuated by liposome clodronate. Increased gene expression of TNF-α and TGF-β observed in obstructed kidneys were markedly attenuated by depletion of renal mononuclear phagocytes. These findings suggest that F4/80 + monocytes /macrophages and/or F4/80 + dendritic cells play a pivotal role in the development of obstruction-induced tubular apoptosis and renal fibrosis, possibly through TNF-α and TGF-β dependent mechanisms.

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