Expression of Angiotensinogen mRNA and Protein in Angiotensin II-Dependent Hypertension

Kobori, Hiroyuki; Lm, Harrison-Bernard; Lg, Navar

doi:10.1681/asn.v123431

Cited by 208 publications

(15 citation statements)

References 38 publications

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“…Furthermore, weak expression of AGT protein was also observed in glomeruli and vasa recta, whereas the distal tubules and collecting ducts are negative. 21–25 Angiotensinogen mRNA is found strongly in the proximal straight tubules. Recent evidence suggests that AGT is constitutively secreted in the proximal straight tubule as in the liver.…”

Section: Intrarenal Ras In Diabetesmentioning

confidence: 99%

Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Kobori

Kamiyama

Harrison‐Bernard

et al. 2013

Journal of Investigative Medicine

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Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of reninangiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy is discussed with a focus on 4 themes: 1) Introduction to RAS cascade, 2) Intrarenal RAS in diabetes, 3) Clinical outcomes of RAS blockade in diabetic nephropathy, and 4) Potential of urinary angiotensinogen (AGT) as an early biomarker of intrarenal RAS status in diabetic nephropathy. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of diabetic nephropathy, and that urinary AGT levels provide an index of intrarenal RAS activity.Keywords diabetic nephropathy; renin-angiotensin system; angiotensinogen; kidney Diabetes affects 220 million people worldwide, including 24 million Americans, and is the 6th leading cause of death in the US. It is associated with increased incidence of functional and structural alterations in the kidneys, eventually leading to end-stage renal failure in many patients. Diabetic nephropathy (DN) is the most common cause of end-stage renal failure in the US, accounting for 45% of patients starting dialysis 1, 2 . Type 2 diabetes mellitus (T2D) is the most common type of diabetes accounting for 90-95% of all diagnosed cases of diabetes and affecting 8% of the US population 3, 4 . Obesity has been identified as the principal risk factor associated with the rising prevalence of T2D 5 . The epidemic proportions of obesity and diabetes justify the enormous effort to identify novel pathways and mechanisms involved in their prevention and treatment. Diabetes is a chronic and debilitating disease that is characterized by progressive albuminuria, declining glomerular RENIN-ANGIOTENSIN SYSTEM (RAS) CASCADEThe importance of the RAS in the regulation of blood pressure (BP) and fluid and electrolyte homeostasis has been well recognized 6,7 . As indicated in Figure 1, the balance between vasoconstrictor and vasodilator effects is determined by the actions of angiotensin II and angiotensin 1-7. The formation of angiotensin II is dependent upon the substrate availability of AGT, angiotensin I and the activities of renin, angiotensin converting enzyme (ACE), ACE2, and ACE-independent enzymatic pathways including serine proteases such as chymase. Angiotensin 1-7 can be formed directly from angiotensin II hydrolyzed by ACE2 or indirectly from angiotensin I via an intermediate step of the formation of angiotensin 1-9 hydrolyzed by ACE2 and ACE in sequence. The actions of angiotensin II are determined by signaling via angiotensin II type 1 (AT1) and type 2 (AT2) receptors 8 and the putative angiotensi...

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Section: Intrarenal Ras In Diabetesmentioning

confidence: 99%

Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Kobori

Kamiyama

Harrison‐Bernard

et al. 2013

Journal of Investigative Medicine

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“…In contrast to the negative influence on ACE2, Ang II increases ACE expression within the kidney (Harrison-Bernard et al 2002;Sadjadi et al 2005b). Ang II also positively influences the expression of its precursor protein angiotensinogen (Kobori et al 2001;Zhang et al 2002), and in selective areas of the kidney, either maintains or up regulates the AT 1 receptor as well (Harrison-Bernard et al 2002). This effect on the AT 1 receptor may also lead to increased renal levels of Ang II via receptor mediated uptake and stable sequestration of the circulating peptide (Ingert et al 2002).…”

Section: Stimulate Inhibitmentioning

confidence: 99%

Role of ACE, ACE2 and Neprilysin in the Kidney

Chappell

2007

Frontiers in Research of the Renin-Angiotensin System on Human Disease

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“…Since inappropriate activation of the intrarenal RAS, which increases intrarenal angiotensin II (Ang II) formation, appears to play a crucial role in the progression of hypertension and associated kidney injury [ 2 , 3 ], mechanisms underlying regulation of intrarenal RAS components have been investigated. In the kidneys of Ang II-infused animals and human renin/human AGT double-transgenic mice, elevated intrarenal angiotensinogen (AGT) expression and urinary AGT levels were observed [ 4 , 5 , 6 ], supporting an intrarenal Ang II-AGT amplifying mechanism in Ang II-dependent hypertension. Thus, augmentation of renal proximal tubular AGT has been regarded as one of the key mechanisms leading to enhanced intrarenal Ang II production in Ang II-dependent hypertension [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Immunosuppression by Mycophenolate Mofetil Mitigates Intrarenal Angiotensinogen Augmentation in Angiotensin II-Dependent Hypertension

Satou

Franco

Dugas

et al. 2022

IJMS

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Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

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Expression of Angiotensinogen mRNA and Protein in Angiotensin II-Dependent Hypertension

Cited by 208 publications

References 38 publications

Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Role of ACE, ACE2 and Neprilysin in the Kidney

Immunosuppression by Mycophenolate Mofetil Mitigates Intrarenal Angiotensinogen Augmentation in Angiotensin II-Dependent Hypertension

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