Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms -AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na + /H + exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.

Abstract. The slow pressor response to prolonged infusions of angiotensin II (AngII) entails a delayed rise in BP. This study investigated the hypothesis that the response depends on the generation of oxidative stress. The BP and renal functional response of mice to graded doses (200, 400, and 1000 ng · kg Ϫ1 · min Ϫ1 ) of subcutaneously infused AngII was studied. The SBP of conscious mice increased by day 3 at AngII1000 but showed a delayed rise by days 9 to 13 (slow pressor response) at the lower rates of AngII infusion. By day 13, there was a graded increase in SBP with the rate of AngII infusion (Vehicle, Ϫ2.6 Ϯ 2.6%; AngII200, ϩ14.1 Ϯ 5.0%; AngII400, ϩ31.9 Ϯ 1.9%; AngII1000, ϩ43.2 Ϯ 5.5%). The MAP measured under anesthesia rose significantly (P Ͻ 0.001) with AngII400 at 14 d (Vehicle, 85 Ϯ 2 mmHg; AngII400, 100 Ϯ 3 mmHg). When studied at day 6, the MAP of AngII400 rats was not elevated (88 Ϯ 2 mmHg; NS versus vehicle), yet the GFR was higher (1.05 Ϯ 0.05 versus 1.25 Ϯ 0.05 ml · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05) accompanied by an increase in the filtration fraction (FF) (28.8 Ϯ 1.2 versus 37.2 Ϯ 0.8%; P Ͻ 0.001). From day 6 through day 14, the MAP had increased (P Ͻ 0.01) in AngII400, accompanied by a significant reduction in GFR to 1.05 Ϯ 0.04 ml · min Ϫ1 · g Ϫ1 (P Ͻ 0.01) and elevation of renal vascular resistance (RVR) (day 6 versus day 14, 15.3 Ϯ 0.6 versus 19.2 Ϯ 1.2 mmHg · ml Ϫ1 · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05). Renal excretion of 8-iso PGF 2␣ was increased in AngII400 group at day 12 (2.52 Ϯ 0.35 versus 5.85 Ϯ 0.78 pg · day Ϫ1 ; P Ͻ 0.01). The permeant superoxide dismutase mimetic tempol reduced the effects of AngII400 on the SBP (Ϫ1.7 Ϯ 5.8%; P Ͻ 0.01), the MAP (87 Ϯ 4 mmHg; P Ͻ 0.01), and the RVR (15.2 Ϯ 0.5 mmHg · ml Ϫ1 · min Ϫ1 · g Ϫ1 ; P Ͻ 0.05) at day 14 and the renal 8-iso PGF 2␣ excretion (3.53 Ϯ 0.71 pg · d Ϫ1 ; P Ͻ 0.05) at day 12. It is concluded that the AngII infused mouse is a valid model for the slow pressor response. There is an early rise in GFR and FF, consistent with increased postglomerular vascular resistance and a late rise in RVR with a fall in GFR, consistent with increased preglomerular vascular resistance that is accompanied by a rise in BP. There is evidence of increased oxidative stress that is implicated in the increase in the BP and RVR in this model.The angiotensin II (AngII) slow pressor response is a gradually developing increase in BP (BP) with an initially subpressor rate of infusion (1-4). The slow pressor response was first described in rats in 1963, (1) and subsequently has been demonstrated in rabbits, dogs and man (5). Whereas the plasma AngII levels increase by about 80-fold during an immediate pressor response, they are elevated within a physiologic level of 2-to sixfold during a slow pressor response (6). A slow pressor response is seen also with the thromboxane A2/prostaglandin H2 (TP) receptor mimetic, U-46619 (7,8). This slow pressor response has been considered an excellent model for renal hypertension in which both AngII type I (AT1) and TP receptor have been implica...

The Rho-ROCK system may play an important role in the development of tissue fibrosis, and the Rho-ROCK signaling pathway may be a new therapeutic target for preventing interstitial fibrosis in progressive renal disease.

CXC chemokine ligand 12 (CXCL12; stromal cell-derived factor 1) is a unique homeostatic chemokine that signals through its cognate receptor, CXCR4. CXCL12/CXCR4 signaling is essential for the formation of blood vessels in the gastrointestinal tract during development, but its contribution to renal development remains unclear. Here, we found that CXCL12-secreting stromal cells surround CXCR4-positive epithelial components of early nephrons and blood vessels in the embryonic kidney. In glomeruli, we observed CXCL12-secreting podocytes in close proximity to CXCR4-positive endothelial cells. Both CXCL12-and CXCR4-deficient kidneys exhibited identical phenotypes; there were no apparent abnormalities in early nephrogenesis or in differentiation of podocytes and tubules, but there was defective formation of blood vessels, including ballooning of the developing glomerular tuft and disorganized patterning of the renal vasculature. To clarify the relative importance of different cellular defects resulting from ablation of CXCL12 and CXCR4, we established endothelial cell-specific CXCR4-deficient mice, which recapitulated the renal phenotypes of conventional CXCR4-deficient mice. We conclude that CXCL12 secreted from stromal cells or podocytes acts on endothelial cells to regulate vascular development in the kidney. These findings suggest new potential therapeutic targets for remodeling the injured kidney. 20: 171420: -172320: , 200920: . doi: 10.1681 Nephrogenesis requires a coordinated process during development and has two distinct embryologic aspects. One is the development of epithelial components. They originate from interactions between the metanephric blastema, a group of mesenchymal cells in the genital ridge, and the ureteric bud (UB), an epithelial outgrowth of the nephric duct. When the tips of the UB invade the metanephric blastema, mutual inductive signals initiate a cascade of events, including UB branching and mesenchymal aggregation, which is followed by formation of nephrons. The other essential aspect is assembly of renal microcirculation, a multistep process including differentiation of endothelial progenitor cells, recruitment of endothelial cells into the glomerular J Am Soc Nephrol

The serum glycoprotein fetuin-A is an important inhibitor of extra-osseous calcification, but correlations between serum fetuin-A levels and the extent of vascular calcification are controversial. In this study, we used a rat model of adenine-induced renal failure with secondary hyperparathyroidism that exhibits all characteristic features of patients with chronic kidney disease. These rats had medial vascular calcification along with reduced levels of both serum and hepatic fetuin-A. Treatment with an inhibitor of ectopic calcification, alendronate, decreased bone turnover and eliminated completely the vascular calcification in this rat model, but there was no change in the levels of hepatic and serum fetuin-A. Centrifugation of the serum of untreated rats with renal failure gave a small precipitate composed of fetuin-A, calcium, magnesium, and phosphate; this complex, absent from normal rat serum, was not found in the serum of alendronate-treated rats with renal failure. Rat serum contained three types of phosphorylated fetuin-A, as well as unphosphorylated forms, but only the fully phosphorylated fetuin-A was present in the mineral complex. The amount of this complex reflected the risk of mineral precipitation. Our results suggest that the measurement of serum fetuin-mineral complex rather than fetuin-A alone might provide a better indication of extra-osseous calcification propensity.

These results strongly suggested the presence of increased oxidative stress in the interstitium of UUO kidneys. The oxidative stress and the formation of various kind of biological active oxidative products in the interstitium are supposed to play significant roles in UUO kidney.

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/ajprenal. 00423.2003.-We investigated the hypothesis that thromboxane A 2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 sc for 14 days) using TP-R knockout (TP Ϫ/Ϫ) and wild-type (ϩ/ϩ) mice. TP Ϫ/Ϫ had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF 2␣) and nitric oxide (NOx). Infusion of ANG II into TP ϩ/ϩ increased ROS and thromboxane B 2 (TxB2) and increased RVR and FF. ANG II infusion into TP Ϫ/Ϫ mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP Ϫ/Ϫ: ϩ6 Ϯ 2 vs. TP ϩ/ϩ: ϩ15 Ϯ 3 mmHg) and failed to increase FF, ROS, or TxB 2 but increased NOx and paradoxically decreased RVR (Ϫ2.1 Ϯ 1.7 vs. ϩ2.6 Ϯ 0.8Blockade of AT1 receptor of TP Ϫ/Ϫ mice infused with ANG II reduced MAP (Ϫ8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT 1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP Ϫ/Ϫ mice have a basal increase in RVR and FF associated with ROS. thromboxane A 2-prostaglandin H2 receptor; isoprostane; hypertension; renal vascular resistance SUBCUTANEOUS ANG II infusion at 400 ng⅐ kg Ϫ1 ⅐min Ϫ1 causes a slow pressor response accompanied by oxygen free radical (O 2 Ϫ ⅐) formation and increased filtration fraction (FF) and renal vascular resistance (RVR). The important role of increased O 2 Ϫ ⅐ formation from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the vasoconstrictor response to ANG II was first showed by Harrison and colleagues (15). We showed later that ANG II increased NADPH oxidase activity in the kidney and the expression of the p22 phox component in the renal afferent arteriole (6, 35). We and others also proposed a significant role for thromboxane A 2 (TxA 2 ) and other ligands for the TxA 2 -PGH 2 receptor (TP-R) in the pressor and renal hemodynamic response to ANG II (17, 18, 20 -22, 40, 42, 43). Under normal conditions, blood pressure (BP) is unaffected by a TxA 2 synthase inhibitor, TP-R blocker, or by TP-R gene knockout (13,28,40). However, during ANG II infusion, there is increased prostaglandin (PG) and TxA 2 generation (19), and blockade of TP-Rs blunts or prevents the pressor response and the increase in RVR (20 -22, 40, 43). However, the conclusion that TP-Rs have a critical role in the response to ANG II depends on the specificity of the drugs used. Therefore, this study was conducted in mice lacking functional TP-Rs by gene deletion.TP-Rs are expressed on systemic blood vessels and renal microvessels, glomeruli, mesangial cells, thick ascending limbs (TALs) of the loops of...