Apoptosis and Glomerular Injury After Prolonged Nitric Oxide Synthase Inhibition in Spontaneously Hypertensive Rats

Abstract

Abstract-This study was designed to investigate the relationship between apoptosis and glomerular injury in spontaneously hypertensive rats (SHR) with hypertensive disease that was exacerbated by inhibition of NO synthesis. Development of glomerular cell apoptosis was evaluated by assessment of renal hemodynamics, glomerular morphometric changes, and participation of the renin-angiotensin system. Three groups of 20-week-old SHR were investigated: control male SHR and 2 similar groups given 2 doses of N G -nitro-L-arginine methyl ester (L-NAME, 50 or 80 mg/L, respectively) for 3 weeks. Mean arterial pressure and renal vascular resistance increased, whereas effective renal plasma flow and glomerular filtration rate were diminished by L-NAME. The small artery wall/lumen ratio increased as the glomerular-tuft area diminished. Renal cortical tissue levels of angiotensin II increased in response to the L-NAME, thereby inducing afferent arteriolar injury. Apoptosis and proliferative index (PCNA) of nonsclerotic glomeruli were induced by the low-dose L-NAME as the glomerular cell number decreased. In contrast, the PCNA index was downregulated with the high-dose L-NAME. These results indicate that angiotensin II activation, induced by L-NAME, was related to glomerular cell deletion and apoptosis together with the pathophysiological changes of severe nephrosclerosis and impaired renal dynamics. (Hypertension. 2001;38:1300-1306.)

Nipradilol Prevents L-NAME-Exacerbated Nephrosclerosis with Decreasing of Caspase-3 Expression in SHR.

“…The fixation pressure was the mean arterial pressure of the rats, approximately 230, 180, and 180 mmHg for the L-NAME, control, and L-NAME/nipradilol groups, respectively as previously described (5,6). Sections (3 µm thick) were stained with hematoxylin-eosin, periodic acidSchiff (PAS), Elastica-Masson, and periodic acid-methenaminesilver reactions for assessment of glomerular and intrarenal vascular injuries, as well as tubulo-interstitial changes, extracellular matrix, fibrinogen, and collagen.…”

“…Sections (3 µm thick) were stained with hematoxylin-eosin, periodic acidSchiff (PAS), Elastica-Masson, and periodic acid-methenaminesilver reactions for assessment of glomerular and intrarenal vascular injuries, as well as tubulo-interstitial changes, extracellular matrix, fibrinogen, and collagen. Grading of the GIS of the juxtamedullary and subcapsular layers were assessed on a scale from 0 to 3: 0 represented no injuries, 1 was glomerular injury of up to one-third, 2 was one-third to two-thirds injury, and 3 was more than two-thirds injured, as previously described (5,6,(16)(17)(18).…”

“…All microscopic slides were examined using a computer analyzer system (Image Quest, Hamamatsu Photonics, Hama-matsu and MacScope; Mitani Co., Fukui, Japan), and calculations were made using stereologic principles (5,6). The AG of the subcapsular and juxtamedullary glomeruli were measured by tracing the outlines of those glomerular capillaries having a vascular pole, and the AT was measured by tracing the luminal area of all capillaries falling within one high power field ( 400), as previously described (5,6).…”

“…The AG of the subcapsular and juxtamedullary glomeruli were measured by tracing the outlines of those glomerular capillaries having a vascular pole, and the AT was measured by tracing the luminal area of all capillaries falling within one high power field ( 400), as previously described (5,6). In addition, the wall thickness was assessed as the ratio of media thickness to the outer radius of afferent arterioles and interlobular arteries, according to our previous report.…”

“…Apoptosis is a recognized pathophysiological phenomenon that contributes to the remodeling of hypertensive coronary disease (1), ischemia/reperfusion-induced myocardial injuries (2) treated with candesartan (3), stroke with neuronal cell death in ischemia and oxygen reperfusion (4), severe nephrosclerosis (5,6), atherosclerosis (7,8), and numerous renal diseases (9). Identification of specific markers for apoptosis in severe nephrosclerosis is critical to the development study by White, when the DNA of mammalian cells was damaged by irradiation or superoxide, the cells responded by activating cell cycle checkpoints by inducing apoptosis or arresting the cell cycle in the G1 and G2 phases (14).…”