Direct Evidence for Intrarenal Chymase-Dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Park, Sungmi; Bivona, Benjamin J.; Ford, Stephen M.; Xu, Sen; Kobori, Hiroyuki; Garavilla, Lawrence de; Harrison‐Bernard, Lisa M.

doi:10.1161/hypertensionaha.111.202424

Cited by 28 publications

(26 citation statements)

References 47 publications

(59 reference statements)

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“…Release of renin by cardiac mast cells can be induced by ischemia resulting in release of norepinephrine and generation of cardiac arrhythmias (222). Furthermore, kidney mast cells can also make chymase which can augment Ang II production and microvascular function in diabetes (286). Still the physiological importance of these mechanisms remains to be determined.…”

Section: Renin In Mast Cellsmentioning

confidence: 99%

Classical Renin‐Angiotensin System in Kidney Physiology

Sparks

Crowley

Gurley

et al. 2014

Comprehensive Physiology

477

429

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The renin-angiotensin system has powerful effects in control of the blood pressure and sodium homeostasis. These actions are coordinated through integrated actions in the kidney, cardio-vascular system and the central nervous system. Along with its impact on blood pressure, the renin-angiotensin system also influences a range of processes from inflammation and immune responses to longevity. Here, we review the actions of the “classical” renin-angiotensin system, whereby the substrate protein angiotensinogen is processed in a two-step reaction by renin and angiotensin converting enzyme, resulting in the sequential generation of angiotensin I and angiotensin II, the major biologically active renin-angiotensin system peptide, which exerts its actions via type 1 and type 2 angiotensin receptors. In recent years, several new enzymes, peptides, and receptors related to the renin-angiotensin system have been identified, manifesting a complexity that was previously unappreciated. While the functions of these alternative pathways will be reviewed elsewhere in this journal, our focus here is on the physiological role of components of the “classical” renin-angiotensin system, with an emphasis on new developments and modern concepts.

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Section: Renin In Mast Cellsmentioning

confidence: 99%

Classical Renin‐Angiotensin System in Kidney Physiology

Sparks

Crowley

Gurley

et al. 2014

Comprehensive Physiology

477

429

View full text Add to dashboard Cite

show abstract

“…In models of hypertension, there is upregulation of ACE and downregulation of ACE2 leading to increased Ang II levels along with reduced Ang 1-7 levels (6;25). However, there are decreased intrarenal levels of ACE in models of diabetes mellitus associated with upregulation of ACE2 (26) and chymase (27). The reduced ACE activity may be partially renoprotective, but the increased chymase provides an alternative pathway for Ang II formation which may contribute to the progression of diabetic nephropathy (27).…”

Section: Regulation Of Intrarenal Rasmentioning

confidence: 99%

Intrarenal renin–angiotensin system in regulation of glomerular function

Navar

2014

Current Opinion in Nephrology and Hypertension

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Purpose of Review The purpose of this review is to provide an update on the current knowledge regarding the role of the intrarenal renin-angiotensin system (RAS) in the regulation of glomerular function including glomerular dynamics and filtration rate, glomerular permeability and structural alterations during chronic increases in intrarenal Ang II. Recent Findings Recent studies have continued to delineate the complex interactions among the various RAS components that participate in regulating glomerular function. While angiotensin (Ang) II acting on AT1 receptors remains as the predominant influence on glomerular dynamics some of these effects are indirectly mediated by Ang II modulating the sensitivity of the macula densa tubuloglomerular feedback mechanism as well as the more recently described feedback mechanism from the connecting tubule. Interestingly, the actions of Ang II on these systems cause opposite effects on glomerular function demonstrating the complexities associated with the influences of Ang II on glomerular function. When chronically elevated, Ang II also stimulates and/or interacts with other factors including reactive oxygen species, cytokines and growth factors and other hormones or paracrine agents to elicit structural alterations. Summary Recent studies have provided further evidence for the presence of many components of the RAS in glomerular structures supporting the importance of locally produced angiotensin peptides to regulate glomerular hemodynamics, filtration rate, macromolecular permeability and contribute to fibrosis and glomerular injury when inappropriately augmented.

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“…Restored migration and NO bioavailability/cGMP production via Mas receptor and decreased NADPH oxidase activity, and enhanced survival and proliferation of CD34 + cells [188] Diabetic wounds NorLeu ( Prevention of obesity, hepatic inflammation and hepatic steatosis induced by a high-fat diet, and improvement in lipid metabolism [191,192] It is worth mentioning that ACE inhibitors fail to completely block AngII formation since many other alternative proteases can still produce AngII and generate hyperglycaemia in the presence of ACE inhibitors [170]. ACE2, on the other hand, acts directly on AngII, irrespective of the pathways involved in the production of this octapeptide.…”

Section: Pathology Experimental Approach Effectmentioning

confidence: 99%

Modulation of the action of insulin by angiotensin-(1–7)

et al. 2014

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The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as obesity, systemic hypertension and dyslipidaemia, defined as the metabolic syndrome. Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between AngII (angiotensin II) and the insulin signalling pathway has been the focus of great interest in the last decade. Indeed, substantial evidence has shown that anti-hypertensive drugs that block the RAS (renin-angiotensin system) may also act to prevent diabetes. Despite its long history, new components within the RAS continue to be discovered. Among them, Ang-(1-7) [angiotensin-(1-7)] has gained special attention as a counter-regulatory hormone opposing many of the AngII-related deleterious effects. Specifically, we and others have demonstrated that Ang-(1-7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that insulin and Ang-(1-7) share a common intracellular signalling pathway. We also address the molecular mechanisms behind the beneficial effects of Ang-(1-7) on AngII-mediated insulin resistance. Finally, we discuss potential therapeutic approaches leading to modulation of the ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7)/Mas receptor axis as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.

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Direct Evidence for Intrarenal Chymase-Dependent Angiotensin II Formation on the Diabetic Renal Microvasculature

Cited by 28 publications

References 47 publications

Classical Renin‐Angiotensin System in Kidney Physiology

Classical Renin‐Angiotensin System in Kidney Physiology

Intrarenal renin–angiotensin system in regulation of glomerular function

Modulation of the action of insulin by angiotensin-(1–7)

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