. Short-term nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury. Am J Physiol Renal Physiol 290: F632-F640, 2006. First published October 4, 2005 doi:10.1152/ajprenal.00259.2005.-Chronic nitric oxide (NO) inhibition and salt overload (HS) promote severe hypertension and renal injury, which regress quickly, although not completely, on treatment withdrawal. We investigated whether renal function and structure remain stable 6 mo after cessation of these treatments. Adult male Munich-Wistar rats were distributed among three groups: HS, receiving 3.1% Na diet; HSϩN, receiving HS and the NO inhibitor N -nitro-L-arginine methyl ester (L-NAME; 30 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 orally); and HSϩNϩL, receiving HSϩN and the ANG II blocker losartan (L; 50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 orally). In studies performed after 20 days of treatment (protocol 1), HSϩN rats exhibited severe glomerular and systemic hypertension, massive albuminuria, glomerular and interstitial injury, and infiltration by macrophages and cells expressing ANG II. These abnormalities were largely prevented in the HSϩNϩL group. A second cohort (protocol 2) received HSϩN for 20 days, followed by a conventional (0.5% Na) diet and no L-NAME treatment during the subsequent 30 days. At this time, systemic and glomerular pressure, along with parameters of renal injury and inflammation, were still higher than in HS or HSϩNϩL rats, although differences were much smaller than in protocol 1. Six months after 20-day L-NAME/salt overload treatment was ceased (protocol 3), severe albuminuria, hypertension, and renal injury developed in HSϩN rats. Again, losartan prevented most of these changes. We conclude 1) short-term HSϩN treatment triggers the autonomous development of progressive glomerulosclerosis; 2) this process may involve activation of the AT 1 receptor; and 3) temporary HSϩN treatment may represent a new model of slowly progressive chronic nephropathy. N-L-nitro-arginine methyl ester; kidney glomerulus/physiopathology; type 1 angiotensin receptor; angiotensin II THE PATHOGENESIS OF CHRONIC nephropathies involves the participation of a host of hemodynamic and inflammatory factors (4,12,15,25,29,36), including glomerular hypertension, infiltration by macrophages and other cell types, and the release of inflammatory mediators such as cytokines, growth factors, and, especially, ANG II. Recent clinical and experimental studies have concentrated on the neutralization of the complex cascade of events leading to chronic nephropathies, seeking to detain, and even to reverse, their progression (10,15,24,30).Several experimental models have been used to address the pathogenesis of progressive nephropathies. Most of these models require complex and laborious procedures, such as surgery or genetic manipulation. A notable exception, in view of its simplicity and reproducibility, is represented by chronic nitric oxide (NO) inhibition, alone or in association with salt overload, which has now been used for over 12 years as a model of hypertension a...
Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.
Background: Inflammatory events antecede established renal injury in rats with 5/6 renal ablation (Nx), as indicated by the beneficial effects of early, uninterrupted treatment with mycophenolate mofetil (MMF). Angiotensin II also exerts a major pathogenic role at this initial phase. We investigated whether losartan (L) or L+MMF treatment, started early, and L+MMF treatment, started late, would exert lasting renoprotection in Nx even after being discontinued. Methods: Adult male Munich-Wistar rats underwent Nx and were divided into three groups: Nx (untreated), NxL (given L), and NxLMMF (given L and MMF). Protocol 1: treatments began on day 1, and ceased on day 30, after Nx. Protocol 2: L+MMF treatment began on day 30 and ceased on day 60. Results: Protocol 1: on day 30, hypertension, albuminuria and renal injury were strongly attenuated in Groups NxL and NxLMMF. On day 120, these abnormalities were still attenuated in group NxLMMF. Protocol 2: on day 120, all parameters were similar between this late NxLMMF group and untreated Nx. Conclusion: In Nx, temporary suppression of early, transitory hemodynamic/inflammatory phenomena affords relatively durable renoprotection even after treatment discontinuation. This effect is not obtained with similar temporary treatment initiated later in the course of renal disease.
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Background: The high sodium consumption continues, and renal disease development is increasing and is a concern. It is a challenge to overcome these two factors simultaneously to control the increase of acute and chronic renal disease. The present study was designed to experimentally evaluate the mesenchymal stem cells (MSC) treatment in ischemia-reperfusion injury under a chronic high sodium environment. Method: Eight weeks old male adult Wistar rats received a normal sodium diet (NSD, 1,3%NaCl) or high sodium diet (HSD, 8,0% NaCl), and renal arteria of both kidneys underwent ischemia and reperfusion (IR) for 45 minutes, or they were submitted to the sham procedure for the control group (SHAM). In both diet groups, we delivered 2x106 MSC (IR+MSC) or phosphate buffer solution (IR+PBS) intraperitoneal at the reperfusion moment. Tail blood pressure (tBP), renal function and histology, and stress oxidative were evaluated after 10 weeks of IR or Sham groups. Results: the blood pressure increased with HSD; however, the MSC treatment decreased it. Although the urea serum increased in the HSD group with MSC treatment, the creatinine clearance increased, and the fraction of sodium excretion decreased. Urine protein and albumin were not different between diet groups. Malondialdehyde (MDA) which evaluates oxidative status, increased, and serum uric acid evaluates anti-oxidative status, decreased with MSC treatment in rats fed HSD. The macrophage (ED1) infiltration decreased with MSC treatment in the renal cortex in both diet groups, while no change was observed in TGF-β. Conclusion: the mesenchymal stem cells recover kidney function even in an adverse high sodium environment, although the oxidative stress increases. This experimental evidence can contribute to following cellular therapy for acute kidney diseases.
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