Effect of Angiotensin II Receptor Blockage on Osteopontin Expression and Calcium Oxalate Crystal Deposition in Rat Kidneys

Abstract

Abstract. Hyperoxaluria leads to calcium oxalate (CaOx) crystallization and development of tubulointerstitial lesions in the kidneys. Treatment of hyperoxaluric rats with angiotensin II (Ang II) type I receptor blocker (ARB) reduces lesion formation. Because Ang II mediates osteopontin (OPN) synthesis, which is involved in both macrophage recruitment and CaOx crystallization, it was hypothesized that ARB acts via OPN. Hyperoxaluria was induced in 10-wk-old male Sprague-Dawley rats, and they were treated with ARB candesartan. At the end of 4 wk, kidneys were examined for crystal deposits, ED-1-positive cells, and expression of OPN mRNA. PCR was used to quantify OPN, renin, and angiotensin-converting enzyme (ACE) mRNA in kidneys. RIA was used to determine renal, plasma, and urinary OPN; plasma renin; Ang II and ACE; and renal Ang II. For evaluating oxidative stress, malondialdehyde was measured. Urinary calcium, oxalate, creatinine, and albumin were also determined. Despite similar urinary calcium and oxalate levels, kidneys of hyperoxaluric rats on candesartan had fewer CaOx crystals, fewer ED-1-positive cells, reduced OPN expression, and reduced malondialdehyde than hyperoxaluric rats. Urinary albumin excretion and serum creatinine levels improved significantly on candesartan treatment. mRNA for OPN, renin, and ACE were significantly elevated in hyperoxaluric rats. OPN synthesis and production increased with hyperoxaluria but to a lesser extent in candesartan-treated hyperoxaluric rats. These results show for the first time that oxalate can activate the renal renin-angiotensin system and that oxalate-induced upregulation of OPN is in part mediated via renal renin-angiotensin system.Oxalate, a by-product of metabolism, is normally excreted in the urine and at low concentrations is harmless to the renal epithelial cells. However, elevated oxalate levels and/or calcium oxalate (CaOx) crystals are injurious (1-3). In addition, exposure of renal epithelial cells in vitro to high levels of oxalate and/or CaOx crystals upregulates the production of chemoattractants osteopontin (OPN) (4) and monocyte-chemoattractant protein-1 (MCP-1) (5, 6). Mild idiopathic hyperoxaluria is associated with CaOx nephrolithiasis, whereas hyperoxaluria resulting from jejunal bypass for obesity or genetic defects in oxalate metabolism is nephrotoxic and produces tubulointerstitial lesions. Tubulointerstitial damage is recognized as one of the most important risk factors for the development of chronic renal diseases and eventual renal failure (7).All components of the renin-angiotensin system (RAS) are produced within the kidney, and intrarenal RAS plays pivotal role in renal disease progression (8). Kidneys produce both angiotensinogen and angiotensin-converting enzyme (ACE), and juxtaglomerular apparatus is the main source of circulating renin. Renin catalyzes the production of angiotensin I, which is converted to angiotensin II (Ang II) by the actions of ACE. Ang II acts through two receptors, types 1 (AT1) and 2 (AT2), and mediates many ...

l-Arginine attenuates the ethylene glycol induced urolithiasis in ininephrectomized hypertensive rats: role of KIM-1, NGAL, and NOs

“…Several studies have confirmed the inhibitory effect of ARBs by suppressing oxidative stress and tubule-interstitial injury through inhibition of osteopontin expression. 103 In this study, administration of telmisartan and cystone showed amelioration in the EG-induced urolithiasis in uninephrectomized hypertensive rats via modulation of ROS; however, it failed to produce any significant down-regulation in the KIM-1 and NGAL mRNA expression. In conclusion, L-arginine showed the nephro-protective and cardioprotective property against EGinduced urolithiasis in uninephrectomized hypertensive rats via modulation of KIM-1, NGAL, eNOs, and iNOs mRNA expression.…”

Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies

“…Recently, we have shown that CaOx crystal deposition in rat kidneys activates the renin-angiotensin system and increases renin expression in the kidneys and serum. 47 Recent studies have shown OPN to be a monocyte chemoattractant specifically for the renal interstitium and that up-regulation of OPN precedes the interstitial monocyte infiltration. 48,49 OPN knockout studies demonstrated a reduced influx of macrophages into obstructed kidneys of knockout mice compared to wild-type mice at days 4 and 7 but not at day 14.…”

Effects of apocynin and losartan treatment on renal oxidative stress in a rat model of calcium oxalate nephrolithiasis

“…The SOD activity in the supernatant of kidney homogenate were measured spectrophotometrically [11] using a kit from the Nanjing Jiancheng Biochemistry (China, Cat:A001) according to the manufacturer's protocol. The concentration of angiotensin II was measured by radioimmunoassay method [22] using a kit from the North Biochemistry Institute (China). The total SOD activity and the total amount of Ang II were corrected by kidney weight.…”

“…Tissue culture studies have indicated involvement of the NADPH oxidase in Ox-induced ROS production and cell injury [10,21]. Furthermore, hyperoxaluria and crystal deposition has been found to activate the renal renin-angiotensin system (RAS) [22][23][24].…”