Intrarenal Renin-Angiotensin System Is Upregulated in Experimental Model of Progressive Renal Disease Induced by Chronic Inhibition of Nitric Oxide Synthesis

Graciano, Miguel Luis; Cavaglieri, Rita de Cássia; Dellê, Humberto; Dominguez, Wagner Vasquez; Casarini, Dulce Elena; Malheiros, Denise Maria Avancini Costa; Noronha, Irene L.

doi:10.1097/01.asn.0000131528.00773.a9

Cited by 116 publications

(126 citation statements)

References 45 publications

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“…L-NAME was purposely chosen because it suppresses plasma renin activity, 10,11 minimizing potential contributions of the systemic RAS. Moreover, in agreement with previous reports, 12 L-NAME increased the renal abundance of several local RAS components, including angiotensinogen, ACE, and the AT 1 receptor. This is likely due to L-NAME-driven renal inflammation and oxidative stress, 28 which can override the physiologic regulation of the local renal RAS and induce its activation.…”

Section: Discussionsupporting

confidence: 80%

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Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Giani

Janjulia

Kamat

et al. 2014

Journal of the American Society of Nephrology

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The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na + /H + exchanger 3, Na + /Pi co-transporter 2, phosphorylated Na + /K + /Cl 2 cotransporter, and phosphorylated Na + /Cl 2 cotransporter; and greater reductions in abundance and processing of the g isoform of the epithelial Na + channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.

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Section: Discussionsupporting

confidence: 80%

“…10,11 Second, previous reports indicate that L-NAME treatment activates the renal RAS. 12 Third, we reasoned it would be important to evaluate the role of the renal ACE/angiotensin II Figure 1. The absence of renal ACE blunts L-NAME-induced hypertension.…”

mentioning

confidence: 99%

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Giani

Janjulia

Kamat

et al. 2014

Journal of the American Society of Nephrology

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“…8,33 Extensive studies indicate that local activation of intrarenal RAS, rather than its systemic levels, dictates tissue damage in the kidneys. 9,35,37,38 Although the importance of intrarenal RAS activation in the evolution of CKD is well established, how RAS components are regulated under pathological conditions remained incompletely understood. In this context, the observations that Klotho represses the expression of all RAS proteins both in vivo and in vitro are quite significant.…”

Section: Discussionmentioning

confidence: 99%

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Zhou

Miao

et al. 2015

The American Journal of Pathology

129

108

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Loss of Klotho and activation of the renin-angiotensin system (RAS) are common pathological findings in chronic kidney diseases. However, whether these two events are intricately connected is poorly understood. We hypothesized that Klotho might protect kidneys by targeted inhibition of RAS activation in diseased kidneys. To test this hypothesis, mouse models of remnant kidney, as well as adriamycin nephropathy and unilateral ureteral obstruction, were utilized. At 6 weeks after 5/6 nephrectomy, kidney injury was evident, characterized by elevated albuminuria and serum creatinine levels, and excessive deposition of interstitial matrix proteins. These lesions were accompanied by loss of renal Klotho expression, up-regulation of RAS components, and development of hypertension. In vivo expression of exogenous Klotho through hydrodynamic-based gene delivery abolished the induction of multiple RAS proteins, including angiotensinogen, renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor, and normalized blood pressure. Klotho also inhibited b-catenin activation and ameliorated renal fibrotic lesions. Similar results were obtained in mouse models of adriamycin and obstructive nephropathy. In cultured kidney tubular epithelial cells, Klotho dose-dependently blocked Wnt1-triggered RAS activation. Taken together, these results demonstrate that Klotho exerts its renal protection by targeted inhibition of RAS, a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders. Chronic kidney disease (CKD) is increasingly recognized as a major public health problem, because it affects about 10% to 13% of the adult population worldwide.1e3 Among many risk factors for developing CKD, aging is an independent and strong predictor for progressive renal insufficiency. 4 The elderly population also tends to develop hypertension and cardiovascular disease, characteristic features consistent with the activation of the renin-angiotensin system (RAS). 5,6 These observations suggest that aging, CKD, and RAS activation might be intimately linked. However, the molecular details behind these connections are not fully understood.RAS consists of several key components, including angiotensinogen (AGT), renin, angiotensin-converting enzyme (ACE), and angiotensin II type I and type II receptors (AT1 and AT2, respectively).7e9 Two main enzymes in this system, renin and ACE, lead to the formation of angiotensin II, the principal active peptide of RAS, which mediates both blood pressureedependent and eindependent kidney damage in CKD. Several factors can induce RAS activation, such as reactive oxygen species, hyperglycemia, and albumin. 10,11 We recently found that all RAS genes contain T cell factor/ lymphoid enhancer-binding factor binding sites in their promoter regions and are directly regulated by canonical Wnt/ b-catenin signaling.12 These results have established that bcatenin is a master regulator controlling the expression of all RAS components in the kidneys.

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“…In animal studies, activation of the intrarenal RAS is an initial response to hypoperfusion and an important contributor to the progression of cardiac and renal injury (26,27). Urinary angiotensinogen (uAGT) has been identified as an indicator of intrarenal RAS activity in both animal and clinical studies (28,29).…”

Section: Introductionmentioning

confidence: 99%

Urinary Biomarkers at the Time of AKI Diagnosis as Predictors of Progression of AKI among Patients with Acute Cardiorenal Syndrome

Chen¹,

Yang

Lei

et al. 2016

CJASN

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Background and objectives A major challenge in early treatment of acute cardiorenal syndrome (CRS) is the lack of predictors for progression of AKI. We aim to investigate the utility of urinary angiotensinogen and other renal injury biomarkers in predicting AKI progression in CRS.Design, settings, participants, & measurements In this prospective, multicenter study, we screened 732 adults who admitted for acute decompensated heart failure from September 2011 to December 2014, and evaluated whether renal injury biomarkers measured at time of AKI diagnosis can predict worsening of AKI. In 213 patients who developed Kidney Disease Improving Global Outcomes stage 1 or 2 AKI, six renal injury biomarkers, including urinary angiotensinogen (uAGT), urinary neutrophil gelatinase-associated lipocalin (uNGAL), plasma neutrophil gelatinase-associated lipocalin, urinary IL-18 (uIL-18), urinary kidney injury molecule-1, and urinary albumin-to-creatinine ratio, were measured at time of AKI diagnosis. The primary outcome was AKI progression defined by worsening of AKI stage (50 patients). The secondary outcome was AKI progression with subsequent death (18 patients).Results After multivariable adjustment, the highest tertile of three urinary biomarkers remained associated with AKI progression compared with the lowest tertile: uAGT (odds ratio [OR], 10.8; 95% confidence interval [95% CI], 3.4 to 34.7), uNGAL (OR, 4.7; 95% CI, 1.7 to 13.4), and uIL-18 (OR, 3.6; 95% CI, 1.4 to 9.5). uAGT was the best predictor for both primary and secondary outcomes with area under the receiver operating curve of 0.78 and 0.85. These three biomarkers improved risk reclassification compared with the clinical model alone, with uAGT performing the best (category-free net reclassification improvement for primary and secondary outcomes of 0.76 [95% CI, 0.46 to 1.06] and 0.93 [95% CI, 0.50 to 1.36]; P,0.001). Excellent performance of uAGT was further confirmed with bootstrap internal validation.Conclusions uAGT, uNGAL, and uIL-18 measured at time of AKI diagnosis improved risk stratification and identified CRS patients at highest risk of adverse outcomes.

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Intrarenal Renin-Angiotensin System Is Upregulated in Experimental Model of Progressive Renal Disease Induced by Chronic Inhibition of Nitric Oxide Synthesis

Cited by 116 publications

References 45 publications

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Renal Angiotensin-Converting Enzyme Is Essential for the Hypertension Induced by Nitric Oxide Synthesis Inhibition

Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System

Urinary Biomarkers at the Time of AKI Diagnosis as Predictors of Progression of AKI among Patients with Acute Cardiorenal Syndrome

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