Major role for ACE-independent intrarenal ANG II formation in type II diabetes

Park, Sungmi; Bivona, Benjamin J.; Kobori, Hiroyuki; Seth, Dale M.; Chappell, Mark C.; Lazartigues, Eric; Harrison‐Bernard, Lisa M.

doi:10.1152/ajprenal.00519.2009

Cited by 82 publications

(102 citation statements)

References 47 publications

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“…17,43 A different possibility is that, in the presence of excess substrate, Ang II might be generated by ACE-independent pathways such as chymase. 44 In summary, our data demonstrate that an enhanced intrarenal ACE-derived Ang II formation, in the absence of systemic ACE, increases kidney, and urinary Ang II levels and induces the progressive development of hypertension. The findings presented here suggest that ACE inhibitors and other RAS blockers with enhanced kidney tissue distribution or specificity may provide a better approach to treat patients with certain forms of hypertension or kidney disease with increased intrarenal RAS activity.…”

Section: Basic Research Wwwjasnorgmentioning

confidence: 54%

Intrarenal Angiotensin-Converting Enzyme Induces Hypertension in Response to Angiotensin I Infusion

González-Villalobos

Billet²,

Kim³

et al. 2011

Journal of the American Society of Nephrology

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The contribution of the intrarenal renin-angiotensin system to the development of hypertension is incompletely understood. Here, we used targeted homologous recombination to generate mice that express angiotensin-converting enzyme (ACE) in the kidney tubules but not in other tissues. Mice homozygous for this genetic modification (ACE 9/9 mice) had low BP levels, impaired ability to concentrate urine, and variable medullary thinning. In accord with the ACE distribution, these mice also had reduced circulating angiotensin II and high plasma renin concentration but maintained normal kidney angiotensin II levels. In response to chronic angiotensin I infusions, ACE 9/9 mice displayed increased kidney angiotensin II, enhanced rate of urinary angiotensin II excretion, and development of hypertension. These findings suggest that intrarenal ACE-derived angiotensin II formation, even in the absence of systemic ACE, increases kidney angiotensin II levels and promotes the development of hypertension. The renin-angiotensin system (RAS), and its main effector angiotensin II (Ang II), are key regulators of sodium and body fluid homeostasis and BP. Moreover, the presence of significant RAS alterations in the development of high BP is supported by the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and AT 1 receptor blockers in the treatment of hypertension and the prevention of organ damage. [1][2][3][4][5] Because the vast majority of hypertensive patients lack consistent signs of systemic RAS activation, 6 there is growing recognition that changes in tissue Ang II production in different organs may be of importance in the development and maintenance of hypertension.Intrarenal Ang II generation might be of particular significance because of its critical role in regulating the kidneys' handling of sodium balance, fluid homeostasis, and BP. Furthermore, high intrarenal Ang II levels are associated with profound changes in kidney function characterized by impairment of renal blood flow and GFR, reductions in sodium excretion, and suppression of the pressure-natriuresis relationship. [7][8][9][10][11] As emphasized by Guyton, 12 the presence of such changes has important consequences for long-term BP regulation because resetting of the pressure-natriuresis relationship and defective sodium handling by the kidneys leads to body fluid dysregulation and represents a final common pathway for maintenance of hypertension. Moreover, although the primary importance of the kidneys in hypertension does not negate the significance of various nonrenal mechanisms in the pathogenesis of this condition, 13 a widely held premise is that hypertension cannot coexist in the presence of normal renal function. 14

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Section: Basic Research Wwwjasnorgmentioning

confidence: 54%

Intrarenal Angiotensin-Converting Enzyme Induces Hypertension in Response to Angiotensin I Infusion

González-Villalobos

Billet²,

Kim³

et al. 2011

Journal of the American Society of Nephrology

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“…In this scenario, transcytotic retrieval, luminal recycling, or intracellular activation of RAS components prevail and may be functionally relevant for endogenous, local Ang I generation. However, because in the proximal convolutions local ACE abundance is minute, local generation of Ang II possibly relies on the activity of other proteases, which could explain the measured, ϳ100-fold elevated intratubular Ang II levels (52,62). Contrastingly, high ACE2 expression levels agree with intensive Ang-(1-7) generation in PCT.…”

Section: Discussionmentioning

confidence: 92%

Intrarenal Renin Angiotensin System Revisited

Pohl

Kaminski

Castrop

et al. 2010

Journal of Biological Chemistry

131

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The existence of a local renin angiotensin system (RAS) of the kidney has been established. Angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), angiotensin receptors, and high concentrations of luminal angiotensin II have been found in the proximal tubule. Although functional data have documented the relevance of a local RAS, the dualism between biosynthesis and endocytotic uptake of its components and their cellular processing has been incompletely understood. To resolve this, we have selectively analyzed their distribution, endocytosis, transcytosis, and biosynthesis in the proximal tubule. The presence of immunoreactive AGT, restricted to the early proximal tubule, was due to its retrieval from the ultrafiltrate and storage in endosomal and lysosomal compartments. Cellular uptake was demonstrated by autoradiography of radiolabeled AGT and depended on intact endocytosis. AGT was identified as a ligand of the multiple ligandbinding repeats of megalin. AGT biosynthesis was restricted to the proximal straight tubule, revealing substantial AGT mRNA expression. Transgenic AGT overexpression under the control of an endogenous promoter was also restricted to the late proximal tubule. Proximal handling of renin largely followed the patterns of AGT, whereas its local biosynthesis was not significant. Transcytotic transport of AGT in a proximal cell line revealed a 5% recovery rate after 1 h. ACE was expressed along late proximal brush-border membrane, whereas ACE2 was present along the entire segment. Surface expression of ACE and ACE2 differed as a function of endocytosis. Our data on the localization and cellular processing of RAS components provide new aspects of the functional concept of a "self-contained" renal RAS.

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“…Our previous work (24,25) demonstrated significantly dilated juxtamedullary afferent arterioles in kidneys of 18-wk-old diabetic mice. We have expanded upon these initial findings and now demonstrate that dilated afferent arterioles could contribute to increased glomerular capillary pressure, hyperfiltration, and renal injury in the db/db model.…”

Section: -Wk-oldmentioning

confidence: 86%

“…EZML-82K, Linco Research; Mercodia Ultrasensitive Mouse Insulin ELISA no. 10-1150-01; Albuwell M ELISA, code 1011 Exocell), respectively, as we have previously described (24,25).…”

Section: Analytic Methodsmentioning

confidence: 99%

Glomerular filtration rate determinations in conscious type II diabetic mice

Bivona

Park

Harrison‐Bernard

2011

American Journal of Physiology-Renal Physiology

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Diabetic nephropathy is a major cause of end-stage renal disease worldwide. The current studies were performed to determine the later stages of the progression of renal disease in type II diabetic mice (BKS; db/db). Methodology was developed for determining glomerular filtration rate (GFR) in conscious, chronically instrumented mice using continuous intravenous infusion of FITC-labeled inulin to achieve a steady-state plasma inulin concentration. Obese diabetic mice exhibited increased GFR compared with control mice. GFR averaged 0.313 Ϯ 0.018 and 0.278 Ϯ 0.007 ml/min in 18-wk-old obese diabetic (n ϭ 11) and control (n ϭ 13) mice, respectively (P Ͻ 0.05). In 28-wk-old obese diabetic (n ϭ 10) and control (n ϭ 15) mice, GFR averaged 0.348 Ϯ 0.030 and 0.279 Ϯ 0.009 ml/min, respectively (P Ͻ 0.05). GFR expressed per gram BW was significantly reduced in 18-and 28-wk-old obese diabetic compared with control mice (5.9 Ϯ 0.3 vs. 9.0 Ϯ 0.3; 6.6 Ϯ 0.6 vs. 7.8 Ϯ 0.3 l·min Ϫ1 ·g body wt Ϫ1 ), respectively (P Ͻ 0.05). However, older nonobese type II diabetic mice had significantly reduced GFR (0.179 Ϯ 0.023 ml/min; n ϭ 6) and elevated urinary albumin excretion (811 Ϯ 127 g/day) compared with obese diabetic and control mice (514 Ϯ 54, 171 Ϯ 18 g/day), which are consistent with the advanced stages of renal disease. These studies suggest that hyperfiltration contributes to the progression of renal disease in type II diabetic mice. renal inulin clearance; plasma volume; intravenous infusion; db/db mouse; Evans blue dye; indicator dilution technique TYPE II DIABETES MELLITUS is the most common endocrine disease affecting 250 million people worldwide (1, 4). Obesity has been identified as the principal risk factor associated with the rising prevalence of type II diabetes (12), which is predicted to reach 9% of the US population by 2025 (2). Diabetic nephropathy, a major cause of end-stage renal disease, is characterized by progressive albuminuria, declining glomerular filtration rate (GFR), and increased risk for cardiovascular disease.The obese leptin receptor-deficient type II diabetic db/db mouse exhibits metabolic disturbances of diabetes mellitus similar to the characteristics of humans, thus making it a valuable model of type II diabetic disease (5,7,16,28). The lack of leptin receptor signaling leads to persistent hyperphagia and obesity. The db/db mouse exhibits hyperleptinemia, hyperinsulinemia, and develops hyperglycemia in association with insulin resistance. Most importantly, this model exhibits a robust albuminuria, renal and glomerular hypertrophy, thick-

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Major role for ACE-independent intrarenal ANG II formation in type II diabetes

Cited by 82 publications

References 47 publications

Intrarenal Angiotensin-Converting Enzyme Induces Hypertension in Response to Angiotensin I Infusion

Intrarenal Angiotensin-Converting Enzyme Induces Hypertension in Response to Angiotensin I Infusion

Intrarenal Renin Angiotensin System Revisited

Glomerular filtration rate determinations in conscious type II diabetic mice

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