Abstract-Intrarenal angiotensin II (Ang II) is regulated by several complex processes involving formation from both systemically delivered and intrarenally formed substrate, as well as receptor-mediated internalization. There is substantial compartmentalization of intrarenal Ang II, with levels in the renal interstitial fluid and in proximal tubule fluid being much greater than can be explained from the circulating levels. In Ang II-dependent hypertension, elevated intrarenal Ang II levels occur even when intrarenal renin expression and content are suppressed. Studies in Ang II-infused rats have demonstrated that augmentation of intrarenal Ang II is due, in part, to uptake of circulating Ang II via an Ang II type 1 (AT 1 ) receptor mechanism and also to sustained endogenous production of Ang II. Some of the internalized Ang II accumulates in the light and heavy endosomes and is therefore potentially available for intracellular actions. The enhanced intrarenal Ang II also exerts a positive feedback action to augment intrarenal levels of angiotensinogen (AGT) mRNA and protein, which contribute further to the increased intrarenal Ang II in hypertensive states. In addition, renal AT 1 receptor protein and mRNA levels are maintained, allowing increased Ang II levels to elicit progressive effects. The increased intrarenal Ang II activity and AGT production are associated with increased urinary AGT excretion rates. The urinary AGT excretion rates show a clear relationship to kidney Ang II content, suggesting that urinary AGT may serve as an index of Ang II-dependent hypertension. Collectively, the data support a powerful role for intrarenal Ang II in the pathogenesis of hypertension. Key Words: renin-angiotensin system Ⅲ angiotensinogen Ⅲ receptors, angiotensin Ⅲ hypertension, experimental I t is an honor and a privilege to be selected to present the Arthur C. Corcoran Memorial Lecture and I greatly appreciate this recognition that has been given to our research group. We all realize, however, that this year is very different for our country. The terrorist attacks have burned the date of September 11, 2001, indelibly in our minds. In the light of these tragic events, it has been difficult to move forward with the ordinary business of our lives. Compared with the sacrifices of the victims and their families, our activities have seemed irrelevant. Aside from moral and financial support, there is little that we personally can do. As scientists, however, we are comforted by the conviction that what we do collectively provides significant long-term benefits to the health and well-being of our citizens. Thus, going about our business and minimizing the disruptions is the most positive response that we can make. In doing so, however, we keep in mind that others less fortunate lost their lives or their loved ones while they were going about the ordinary business of their lives.As a renal physiologist, receiving this Corcoran Award is particularly meaningful because Dr. Corcoran performed so many interesting studies related to ...
Abstract-Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II-infused rats. Kidneys from sham (nϭ9) and Ang II-infused (80 ng/kg per minute, 13 days, nϭ10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181Ϯ4 versus 115Ϯ5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II-infused rats compared with sham (0.1Ϯ0.1 versus 1.0Ϯ0.1 relative ratio) but increased in distal nephron segments (6.4Ϯ1.4 versus 1.0Ϯ0.1 cortex; 2.5Ϯ0.3 versus 1.0Ϯ0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II-infused rats compared with that of sham (0.4Ϯ0.2 versus 1.0Ϯ0.4) rats but higher in the kidney medulla (1.2Ϯ0.4 versus 1.0Ϯ0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang II-dependent hypertension. Key Words: renin Ⅲ angiotensin II Ⅲ angiotensinogen Ⅲ immunohistochemistry Ⅲ Western blot R enin is synthesized primarily by the juxtaglomerular apparatus (JGA). 1 However, renin mRNA and protein have been detected in proximal, connecting tubule and collecting duct cells of human and mouse kidneys as well as in extrarenal tissues. [2][3][4][5][6][7] Although regulation of renin synthesis and secretion from JGA cells has been extensively studied, 1,8 -13 very little is known about the regulation of tubular renin. 7,14 -16 Renin formation in tubular segments may have greater importance than previously thought in view of evidence of high concentrations of angiotensinogen (AGT), as well as angiotensin (Ang) I and Ang II in proximal tubule fluid, 17,18 and in view of the enhancement of renal AGT mRNA and protein levels in Ang II-dependent hypertension. 19,20 Recent studies in Ang II-infused hypertensive rats have shown that there is an increased urinary excretion of AGT, 21 which is closely correlated with intrarenal Ang II content. 21 Enhancement of urinary AGT excretion suggests increased distal nephron AGT delivery and subsequent Ang I and Ang II formation as long as there is availability of an adequate...
Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.
Abstract-Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenalAng II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT 1 receptor-dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT 1 receptor antagonist, candesartan, prevents this accumulation. Compared with controls (nϭ12; 114Ϯ2 mm Hg), Ang II-infused rats (nϭ12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185Ϯ4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348Ϯ58 versus 119Ϯ16 fmol/mL) and 2-fold (399Ϯ39 versus 186Ϯ26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100Ϯ283 versus 71Ϯ12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88Ϯ22 versus 37Ϯ7 fmol/mg protein T he importance of angiotensin II (Ang II) in the development and maintenance of hypertension is well documented in several animal models of experimental hypertension, such as two-kidney, one-clip renal hypertension (2K1C), the Ren-2 gene transgenic rats, and the Ang IIinfused model. [1][2][3][4] The Ang II-dependent increases in arterial blood pressure are commonly associated with higher levels of circulating and intrarenal Ang II levels, structural abnormalities, and functional derangements in the kidney. [1][2][3][4][5][6] One important feature in the renin-angiotensin system profile observed in these rats is that renal Ang II levels are greater than can be explained on the basis of circulating Ang II and suppressed renin expression. 2,4,[7][8][9] This suggests that angiotensin peptides continue to be generated intrarenally via a renin-independent pathway, or that circulating Ang II accumulates in one or more compartments within the kidney. 4,9 Previous studies have shown that intrarenal Ang II levels are increased in the contralateral nonclip kidney of 2K1C hypertensive rats and in kidneys of Ang II-infused rats and Ren-2 transgenic rats. 2,4,[7][8][9] Because blockade of the AT 1 receptor with losartan normalizes blood pressure and prevents augmentation of intrarenal Ang II levels, this enhanced uptake of Ang II within the kidney appears to be mediated by the AT 1 receptor. 9,10 These results suggest that Ang II levels are augmented in intracellular compartments by an AT 1 receptormediated internalization mechanism and are protected from degradation to some extent.Recent studies have localized angiotensin peptides in renal endosomes and intermicrovillar clefts, thus implicating them as potential sites for intracellular accumulation in the kid-
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