Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes

Cherney, David Z.I.; Xiao, Fengxia; Zimpelmann, Joseph; Har, Ronnie; Lai, Vesta; Scholey, James W.; Reich, Heather N.; Burns, Kevin D.

doi:10.1139/cjpp-2014-0065

Cited by 23 publications

(23 citation statements)

References 10 publications

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“…5,6 While there are no data available for the latter, in humans, elevated sACE2 has been reported in the periphery in heart failure, 23,24 hypertension, 24 severe acute respiratory syndrome 25 and Type 1 diabetes. 26 Here, we provide evidence of increased sACE2 in CSF, correlated with elevated systolic BP, in hypertensive patients. Despite a lack of direct evidence, the similarity between sACE2 and TNFα profiles ( Figure 1C, D) in the CSF of these patients, points to ADAM17-mediated shedding.…”

Section: Discussionmentioning

confidence: 51%

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Sriramula

Xia

et al. 2017

Circulation Research

160

166

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Rationale Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated. Objective To assess the clinical relevance of this ADAM17-mediated ACE2 shedding in hypertensive patients and further identify the cell types and signaling pathways involved in this process. Methods and Results Using a mass spectrometry-based assay, we identified ACE2 as the main enzyme converting Ang II into Ang-(1–7) in human cerebrospinal fluid (CSF). We also observed an increase in ACE2 activity in the CSF of hypertensive patients, which was correlated with systolic blood pressure. Moreover, the increased level of tumor necrosis factor (TNF)-α in those CSF samples confirmed that ADAM17 was up-regulated in the hypertensive patients’ brain. To further assess the interaction between brain renin-angiotensin system and ADAM17, we generated mice lacking Angiotensin II type 1 receptors (AT1R) specifically on neurons. Our data reveal that despite expression on astrocytes and other cells types in the brain, ADAM17 up-regulation during DOCA-salt hypertension occurs selectively on neurons and neuronal AT1R are indispensable to this process. Mechanistically, reactive oxygen species (ROS) and extracellular signal-regulated kinase (ERK) were found to mediate ADAM17 activation. Conclusions Our data demonstrate that AT1R promote ADAM17-mediated ACE2 shedding in the brain of hypertensive patients, leading to a loss in compensatory activity during neurogenic hypertension.

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Section: Discussionmentioning

confidence: 51%

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Sriramula

Xia

et al. 2017

Circulation Research

160

166

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“…A majority of studies, except the one from Ye M, have confirmed that tubular ACE2 decreased significantly in diabetic patients and animal models [7,8,9]. On the other hand, UACE2 excretion significantly increased in uncomplicated type 1 diabetic patients, insulin-resistant subjects, CKD patients and renal transplant recipients, indicating it might be a potential marker for diabetes and kidney disease [13,14,15,23]. Consistent with these studies, we showed that UACE2/Cr levels were much higher in type 2 DN patients.…”

Section: Discussionmentioning

confidence: 99%

Urinary Angiotensin Converting Enzyme 2 Increases in Patients With Type 2 Diabetic Mellitus

Liang¹,

Deng²,

Bi³

et al. 2015

Kidney Blood Press Res

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Background/Aims: Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and recognized to be renoprotective by degrading Angiotensin II to Angiotensin (1-7) in diabetic nephropathy. However, little is known about the role of urinary ACE2 (UACE2) in diabetes. The present study was performed to evaluate UACE2 levels in type 2 diabetic patients with various degrees of albuminuria and its associations with metabolic parameters. The effect of RAS inhibitors on UACE2 excretion was also assessed. Methods: A total of 132 type 2 diabetic patients with different degrees of albuminuria and 34 healthy volunteers were studied. UACE2 levels and activity were measured. Results: Compared to healthy controls, UACE2 to creatinine (UACE2/Cr) levels were significantly increased in both albuminuric and non-albuminuric diabetic patients. UACE2/Cr levels were much higher in hypertensive diabetic patients compared with their normotensive counterparts and treatment with RAS inhibitors markedly attenuated the augmentation. Furthermore, UACE2/Cr was positively correlated with fasting blood glucose, hemoglobin A1C (HbA1C), triglyceride, and total cholesterol. In multiple regression analysis, UACE2/Cr was independently predicted by HbA1C and RAS inhibitors treatment. Conclusions: UACE2 increased in type 2 diabetic patients with various degrees of albuminuria and RAS inhibitors suppresses UACE2 excretion. UACE2 might potentially function as a marker for monitoring the metabolic status and therapeutic response of RAS inhibitors in diabetes.

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“… 18 22 23 Therefore, we proposed a descriptive case study to examine the effect of SGLT2 inhibitors on urinary angiotensinogen excretion in patients with type 2 diabetes. We found that the baseline urinary total angiotensinogen/creatinine ratio in patients with type 2 diabetes was approximately 50 µg/g, which is much higher than in patients with type 1 diabetes, 24 25 suggesting that intrarenal RAS is activated by augmentation of angiotensinogen. Our data also showed that urinary total angiotensinogen/creatinine ratio tended to be decreased by the administration of SGLT2 inhibitors, although the difference of total urinary angiotensinogen/creatinine ratio was not statistically significant.…”

Section: Discussionmentioning

confidence: 75%

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Urinary Excretion of Intact and Total Angiotensinogen in Patients with Type 2 Diabetes

Yoshimoto

Furuki²,

Kobori

et al. 2017

Journal of Investigative Medicine

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We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin–angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6±58.9 to 29.2±60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin–angiotensin system in patients with type 2 diabetes.

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Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes

Cited by 23 publications

References 10 publications

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Urinary Angiotensin Converting Enzyme 2 Increases in Patients With Type 2 Diabetic Mellitus

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Urinary Excretion of Intact and Total Angiotensinogen in Patients with Type 2 Diabetes

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Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes

Cited by 23 publications

References 10 publications

Clinical Relevance and Role of Neuronal AT 1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT 1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Urinary Angiotensin Converting Enzyme 2 Increases in Patients With Type 2 Diabetic Mellitus

Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Urinary Excretion of Intact and Total Angiotensinogen in Patients with Type 2 Diabetes

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Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Clinical Relevance and Role of Neuronal AT ₁ Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension