Overexpression of Inducible Nitric Oxide Synthase in the Kidney of the Spontaneously Hypertensive Rat

Abstract

In kidney, nitric oxide (NO) produced by nitric oxide synthase (NOS) regulates sodium and water excretion and renal medullary blood flow. However, excessive NO production causes nitrative damage and oxidative stress. Since oxidative stress may be linked to hypertension, we examined the expression and activity of inducible NOS (iNOS) in the kidney of the spontaneously hypertensive rat (SHR) and compared our findings to control normtotensive Wistar Kyoto (WKY) rat. Compared with WKY rat, there was significant (p < .05) overexpression (by 96%) and increased (2-fold) activity of iNOS in the cortex but not in the outer medulla, of SHR kidney; in the inner medulla, there was a 6.9-fold increase in iNOS activity in SHR. Increased expression (by 104%) and activity (3.3-fold) of iNOS was specifically observed in proximal tubules (PTs) of the cortex, accompanied by higher (2-fold) tissue nitrite levels. Although certain antioxidant enzymes such as catalase and Mn-superoxide dismutase were overexpressed, glutathione peroxidase was underexpressed in SHR PTs. Overexpression of the inducer of the iNOS promoter, nuclear factor-kappaB (NF-kappaB), with elevated nitrotyrosinylated proteins, further confirmed an elevated state of iNOS-induced oxidative stress in SHR kidneys, possibly signifying its role in the maintenance of essential hypertension seen in these animals.

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“…4). iNOS is known to be a proinflammatory enzyme, and its expression increases in response to various cellular stresses [10]. Several reports have demonstrated that in hypertension, iNOS is overexpressed in the aorta and epithelial cells of the kidney [10,11,[30][31][32].…”

“…Since iNOS and COX-2 are known to be proinflammatory enzymes [10,14], to examine the effect of ABSC treatment on inflammation, we Immunoreactive bands corresponding to iNOS and COX-2 were seen at 130 and 72 kDa, respectively, in the proteins extracted from the aorta. The protein abundance of both iNOS and COX-2 in untreated SHR increased as compared with that in untreated WKY rats.…”

“…O 2 − is produced by various enzymes, particularly by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, in the endothelium and smooth muscle cells of the arteries. Excess O 2 − forms peroxynitrite (ONOO − ), interacting with inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO), and induces endothelial dysfunction and change in vascular response [10,11]. It is known that several inflammatory events occur with the development of hypertension; for example, the expressions of proinflammatory enzymes and cytokines are up-regulated, and the infiltration of immune cells increases, mainly in the kidney and vessels [10,12].…”

“…Excess O 2 − forms peroxynitrite (ONOO − ), interacting with inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO), and induces endothelial dysfunction and change in vascular response [10,11]. It is known that several inflammatory events occur with the development of hypertension; for example, the expressions of proinflammatory enzymes and cytokines are up-regulated, and the infiltration of immune cells increases, mainly in the kidney and vessels [10,12]. Several studies have reported the accumulation of macrophages, neutrophils, and lymphocytes in accordance with the overexpression of macrophage chemoattractant protein-1 (MCP-1) and its receptor C-C chemokine receptor 2 (CCR2), iNOS and cyclooxygenase-2 (COX-2) in models of experimental hypertension [13][14][15][16].…”

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“…Vaziri et al used young SHR in order to attempt to discern the effects of PHTN on NO metabolism and reported significant increases in uNOx, eNOS, and iNOS [29] . Kumar et al reported an overproduction of iNOS in the cortex, inner medulla, and proximal tubules of SHR [30] . They also separately showed that eNOS and nNOS expressions were decreased in the inner medulla and renal cortex [31] .…”