Short-term nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury

Abstract

. 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...

Persistent Hypertension and Progressive Renal Injury Induced by Salt Overload After Short Term Nitric Oxide Inhibition

“…However, the regression of renal injury in this model is incomplete. Previous observations of this model 5 showed that the density of cells staining positively for AngII never returned to baseline and that these rats exhibited progressive albuminuria and hypertension, as well as severe glomerular and interstitial injury, when followed for an additional 6 months. These observations suggest that even a short-term treatment with an NO inhibiter in association with salt overload can lead to subtle changes that culminate in the insidious development of chronic kidney disease.…”

“…5,6,10,17 This appears to be a paradox since salt overload would be expected to suppress circulating renin and angiotensin II. However, local production of angiotensin II also occurs at the diseased renal tissue, as shown in several models of chronic kidney disease, even when salt intake is increased.…”

“…[1][2][3] Previous observations 4,5,6 suggested that these abnormalities were reversible upon cessation of treatments. However, recent observations indicate that this recovery is incomplete, and that the persistence of several inflammatory elements heralds the development of chronic kidney disease and progressive renal insufficiency in these animals.…”

“…However, recent observations indicate that this recovery is incomplete, and that the persistence of several inflammatory elements heralds the development of chronic kidney disease and progressive renal insufficiency in these animals. 5 Dietary salt overload is known to exacerbate renal injury initiated by a host of other mechanisms. 4,7 The mechanisms responsible for this effect are unclear.…”

5/6th Nephrectomy in Combination with High Salt Diet and Nitric Oxide Synthase Inhibition to Induce Chronic Kidney Disease in the Lewis Rat

“…Risk factors for CKD invariably impact on endothelial function 5 . We used a rat strain (Lewis) that is relatively resistant to development of CKD and therefore we combined removal of 5/6th of renal mass with nitric oxide (NO) depletion 6,7,8 and a high salt diet 9 . After arrival and acclimatization, animals receive a NO synthase inhibitor (L-NNA) supplemented to drinking water (20 mg/L) for a period of 4 weeks, followed by right sided uninephrectomy (UNX) with continuation of L-NNA after two days.…”