Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus

Aqeel, Sheeba Ba; Ye, Minghao; Wysocki, Jan; Sánchez-Nadales, Alejandro; Khattab, Ahmed; Lores, Enrique; Rademaker, Alfred; Gao, Xiaoyu; Bebu, Ionut; Nelson, Robert G.; Molitch, Mark E.; Batlle, Daniel; Control, Complications Trial Diabetes

doi:10.14814/phy2.14242

Cited by 9 publications

(11 citation statements)

References 57 publications

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“…We speculate that disease conditions where the local kidney RAS is over-active would be the natural target. Several studies using diabetic models show activation of the RAS locally within the kidney by glucose, including an increase in Ang II production [33][34][35][36]. Additional evidence comes from findings of increased RAS components in the kidney and urines from rodent models of diabetic kidney disease (DKD) and in patients with DKD [16,37] and non-diabetic CKD [38,39].…”

Section: Discussionmentioning

confidence: 99%

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

2019

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ACE2 is a monocarboxypeptidase which generates Angiotensin (1-7) from Angiotensin II (1-8). Attempts to target the kidney Renin Angiotensin System using native ACE2 to treat kidney disease are hampered by its large molecular size, 100 kDa, which precludes its glomerular filtration and subsequent tubular uptake. Here, we show that both urine and kidney lysates are capable of digesting native ACE2 into shorter proteins of~60-75 kDa and then demonstrate that they are enzymatically very active. We then truncated the native ACE2 by design from the C-terminus to generate two short recombinant (r)ACE2 variants (1-605 and 1-619AA). These two truncates have a molecular size of~70 kDa, as expected from the amino acid sequence and as shown by Western blot. ACE2 enzyme activity, measured using a specific substrate, was higher than that of the native rACE2 (1-740 AA). When infused to mice with genetic ACE2 deficiency, a single i.v. injection of 1-619 resulted in detectable ACE2 activity in urine, whereas infusion of the native ACE2 did not. Moreover, ACE2 activity was recovered in harvested kidneys from ACE2-deficient mice infused with 1-619, but not in controls (23.1 ± 4.3 RFU/µg creatinine/h and 1.96 ± 0.73 RFU/µg protein/hr, respectively). In addition, the kidneys of ACE2-null mice infused with 1-619 studied ex vivo formed more Ang (1-7) from exogenous Ang II than those infused with vehicle (AUC 8555 ± 1933 vs. 3439 ± 753 ng/mL, respectively, p < 0.05) further demonstrating the functional effect of increasing kidney ACE2 activity after the infusion of our short ACE2 1-619 variant. We conclude that our novel short recombinant ACE2 variants undergo glomerular filtration, which is associated with kidney uptake of enzymatically active proteins that can enhance the formation of Ang (1-7) from Ang II. These small ACE2 variants may offer a potentially useful approach to target kidney RAS overactivity to combat kidney injury.

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Section: Discussionmentioning

confidence: 99%

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

2019

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“…UAGT correlates with ACR ( Terami et al, 2013 ; Satirapoj et al, 2014 ; Park et al, 2015b ; Zhuang et al, 2015 ; Lee et al, 2017 ; Ba Aqeel et al, 2019 ).…”

Section: Intrarenal Ras and Diseasementioning

confidence: 99%

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

et al. 2022

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E.J.H.). A.N. has received consulting fees, speaking honoraria, or both from Daiichi-Sankyo, Taisho, AstraZeneca, Tanabe-Mitsubishi, and Kowa. A.N. received research funds from Boehringer-Ingelheim, Daiichi-Sankyo, Taisho, and Bayer. A.H.J.D. received research funds from Alnylam Pharmaceuticals. D.B. is coinventor of patents entitled "Active low molecular weight variants of angiotensin converting enzyme 2," "Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2) for the treatment of diseases and conditions of the eye," and "Shorter soluble forms of angiotensin converting enzyme 2 (ACE2) for treating and preventing coronavirus infection." D.B. is founder of Angiotensin Therapeutics Inc. D.B. has received consulting fees from AstraZeneca, Relypsa, and Tricida, all unrelated to this work.1 H.L. and F.G. contributed equally to this work. dx.

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“…Urinary renin and AGT have been proposed as biomarkers for intra-renal status of RAS activation 25 , 26 . Furthermore, the presence of urinary AGT precedes the development of Stage 3 CKD in patients with type 1 diabetes 27 .…”

Section: Introductionmentioning

confidence: 99%

Augmented transcripts of kidney injury markers and renin angiotensin system in urine samples of overweight young adults

Rivera

Miranda

Roldán

et al. 2020

Sci Rep

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Obesity has been firmly established as a major risk factor for common disease states including hypertension, type 2 diabetes mellitus, and chronic kidney disease. Increased body mass index (BMI) contributes to the activation of both the systemic and intra-tubular renin angiotensin systems (RAS), which are in turn associated with increased blood pressure (BP) and kidney damage. In this cross-sectional study, 43 subjects of normal or increased body weight were examined in order to determine the correlation of BMI or body fat mass (BFM) with blood pressure, fasting blood glucose (FBG), and urinary kidney injury markers such as interleukin-18 (IL-18), connective tissue growth factor (CTGF), neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 (KIM-1). Our results showed that: (1) subjects with increased body weight showed significantly higher BP, BFM, total body water and metabolic age; (2) BMI was positively correlated to both systolic (R2 = 0.1384, P = 0.01) and diastolic BP (R2 = 0.2437, P = 0.0008); (3) BFM was positively correlated to DBP (R2 = 0.1232, P = 0.02) and partially correlated to urine protein (R2 = 0.047, P = 0.12) and FBG (R2 = 0.07, P = 0.06); (4) overweight young adults had higher urinary mRNA levels of renin, angiotensinogen, IL-18 and CTGF. These suggest that BMI directly affects BP, kidney injury markers, and the activation of the intra-tubular RAS even in normotensive young adults. Given that BMI measurements and urine analyses are non-invasive, our findings may pave the way to developing a new and simple method of screening for the risk of chronic kidney disease in adults.

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Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus

Cited by 9 publications

References 57 publications

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

Novel Variants of Angiotensin Converting Enzyme-2 of Shorter Molecular Size to Target the Kidney Renin Angiotensin System

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Augmented transcripts of kidney injury markers and renin angiotensin system in urine samples of overweight young adults

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