In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system.

Ingelfinger, Julie R.; Zuo, W M; Fon, E A; Ellison, Kristin E.; Dzau, Victor J.

doi:10.1172/jci114454

Cited by 313 publications

(219 citation statements)

References 24 publications

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“…The results described by Ohashi et al, in addition to previous studies from Kobori's group that found elevated urinary AGT levels in patients with chronic kidney disease including patients with diabetes, confirm that urinary AGT levels can function as an Proximal tubule ACE, AGT, AII, Ang 1-7, renin, renin pro-receptor, AT1 6,7 Distal tubule AGT, AII 8 Collecting duct ACE, AGT, AII, Ang 1-7, renin, renin pro-receptor, AT1 8,9 Abbreviations: ACE, angiotensin I-converting enzyme; AGT, angiotensinogen; Ang II receptors; AT-1 and AT-2 subtypes; RAS, rennin-angiotensin system.…”

Section: Are There Clinical Implications For Increased Intrarenal Agt?supporting

confidence: 68%

“…1,2 In addition to the well-characterized systemic RAS, the presence of a local intrarenal RAS has now been generally accepted. The mRNA and functional proteins of the RAS, including angiotensinogen (AGT), renin, prorenin receptor, 3 angiotensin I-converting enzyme and Ang II receptors (AT-1 and AT-2 subtypes), are expressed in rat mesangial cells, 4,5 mouse and rat immortalized renal proximal tubular cells 6,7 and rat collecting duct cells 8,9 (Table 1).…”

mentioning

confidence: 99%

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Upregulation of intrarenal angiotensinogen in diabetes

Casarini

2010

Hypertens Res

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Section: Are There Clinical Implications For Increased Intrarenal Agt?supporting

confidence: 68%

mentioning

confidence: 99%

Upregulation of intrarenal angiotensinogen in diabetes

Casarini

2010

Hypertens Res

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“…47,48,50,52 Proximal tubular cells express mRNA [54][55][56] and protein 53,57 for ACE and Aogen. [58][59][60][61] In vivo evidence that proximal tubular cells may synthesize Ang II has also been reported. 62 The above studies indicate the presence of a functional renal tubular RAAS, which likely has an important function in regulating sodium and fluid balance, and hence BP.…”

Section: Intrarenal Raasmentioning

confidence: 88%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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“…The proximal tubular epithelium expresses AGTN in the normal kidney and in some diseased kidneys. 7,31 However, in the fibrosing kidney, the interstitial FbLCs may produce AGTN rather than the proximal tubular epithelial cells because of significant degeneration of the latter. These dynamic changes in REN and AGTN suggest that the enzymesubstrate reaction occurs in the fibrosing kidney.…”

Section: Discussionmentioning

confidence: 99%

Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

Okada

Inoue

Kanno

et al. 2002

The American Journal of Pathology

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Recently, the renin-angiotensin system (RAS) was implicated in organ fibrosis. However, few studies have examined the localization of RAS components, such as angiotensin II receptors, renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney. To localize these components in the fibrosing kidney, we used a murine model of renal fibrosis that shows an enhanced expression of angiotensin II type 1A receptor (AT 1A R) and AGTN. Our results indicate that the overall expression of angiotensin II type 2 receptor (AT 2 R) and ACE was attenuated in this model, whereas REN expression was unchanged. In addition to tubular epithelial cells that were positive for AT 1A The activation of angiotensin II receptors by angiotensin II has been reported to contribute to the progression of renal fibrosis. 1-3 The intrarenal renin-angiotensin system (RAS) was described in the 1980's, 4 and the kidney contains angiotensin II at a significantly higher level than serum. 5 Although the intrarenal RAS may be altered in some diseased states, 6 -12 the localization of each component of the RAS, such as angiotensin II type 1 and type 2 receptors (AT 1 R and AT 2 R), renin (REN), angiotensinogen (AGTN), and angiotensin-converting enzyme (ACE), in the fibrosing kidney is undefined. In this study, we use immunocytochemical analysis and in situ hybridization techniques to identify cells expressing the RAS components in a murine model of advanced interstitial fibrosis of the kidney. Materials and Methods Murine Model of Renal FibrosisWe used 5-week-old mice that are transgenic for transforming growth factor (TGF)-␤1 13 and that had undergone a subtotal nephrectomy as a model of renal fibrosis. These mice reproducibly develop significant interstitial fibrosis at 12 weeks after surgery. Sham-operated TGF-␤1 transgenic mice were used as controls. We confirmed that the control transgenic mice did not show any significant fibrosis in the kidney by 17 week of age. After 17 weeks, the control mice randomly develop renal fibrosis. At 12 weeks after renoablation, half of each kidney was fixed using 4% paraformaldehyde in phosphatebuffered saline overnight. A portion of each fixed specimen was processed into paraffin blocks for histopathology. The rest of the fixed tissue was rinsed in serial concentrations of sucrose, and then snap-frozen in preparation for immunostaining and in situ hybridization. Total RNA was extracted from the homogenates of the other half of each kidney using TRIzol (Life Technologies, Inc., Grand Island, NY) according to the manufacturer's instructions.

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In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system.

Cited by 313 publications

References 24 publications

Upregulation of intrarenal angiotensinogen in diabetes

Upregulation of intrarenal angiotensinogen in diabetes

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Interstitial Fibroblast-Like Cells Express Renin-Angiotensin System Components in a Fibrosing Murine Kidney

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