No abstract

Abstract-Chronic infusion of angiotensin (Ang) II leads to the development of hypertension and enhances intrarenal Ang II content to levels greater than can be explained from the circulating concentrations of the peptide. We previously reported that renal angiotensinogen (Ao) mRNA is enhanced in Ang II-dependent hypertension and may contribute to augmented intrarenal Ang II levels, but the Ao protein levels were not significantly increased. Because a high-salt diet (H/S) has been shown to suppress renal expression of Ao mRNA, we examined the effects of chronic Ang II infusion on kidney and liver Ao mRNA and protein levels in male Sprague-Dawley rats (nϭ12) maintained on an 8% salt diet. Ang II was administered via osmotic minipumps (40 ng/min) to 1 group (nϭ6) while the remaining rats were sham-operated. A H/S diet alone did not alter systolic blood pressure in sham animals (109Ϯ6 mm Hg at day 12); however, Ang II infusions to the H/S rats significantly increased systolic blood pressure (167Ϯ7 at day 12) and intrarenal Ang II content (459Ϯ107 fmol/g versus 270Ϯ42) despite a marked suppression of plasma renin activity (0.9Ϯ0.2 ng Ang I ⅐ mL Ϫ1 ⅐ h Ϫ1 versus 2.8Ϯ1.3). Ang II infusions significantly increased kidney Ao mRNA compared with the H/S diet alone by 1.9Ϯ0.1-fold. Western blot analysis of kidney protein extracts showed that the Ang II-infused rats had increased kidney Ao protein levels compared with the H/S diet alone (1.9Ϯ0.1-fold). Liver Ao mRNA and protein and plasma Ao protein were also significantly increased by Ang II infusions. These data demonstrate the effects of Ang II infusion to stimulate Ao mRNA and protein. Thus, the augmented intrarenal Ang II in Ang II-dependent hypertension may result, in part, by a positive amplification mechanism to activate renal expression of Ao.

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 ...