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Daniel Batlle - One of the best experts on this subject based on the ideXlab platform.
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novel variants of angiotensin converting enzyme 2 of shorter molecular size to target the Kidney Renin angiotensin system
Biomolecules, 2019Co-Authors: Jan Wysocki, Arndt Schulze, Daniel BatlleAbstract: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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abstract 099 novel angiotensin converting enzyme 2 ace2 truncates to target the Kidney Renin angiotensin system ras
Hypertension, 2019Co-Authors: Jan Wysocki, Arndt Schulze, Ming Zhao, Chad R Haney, Daniel BatlleAbstract:ACE2 is an enzyme with a molecular size of more than 100 kDa which produces Angiotensin (1-7) from Angiotensin II (1-8). Attempts to target Kidney RAS using ACE2 to treat Kidney disease are hampere...
Jacqueline K. Phillips - One of the best experts on this subject based on the ideXlab platform.
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renal denervation does not affect hypertension or the Renin angiotensin system in a rodent model of juvenile onset polycystic Kidney disease clinical implications
Scientific Reports, 2021Co-Authors: Cara M. Hildreth, Ahmed A. Rahman, Sean A. Barton, Benjamin F. Wyse, Chai K. Lim, Paul M. Pilowsky, Jacqueline K. PhillipsAbstract:We examined the effect of total and afferent renal denervation (RDN) on hypertension and the Renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic Kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and Kidney Renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; Kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P < 0.001, n = 26). These parameters were not affected by RDN. Intrarenal mRNA expression levels of Renin, angiotensinogen, angiotensin-converting enzyme (ACE)2, and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs. Lewis (all P < 0.05, n = 26). This pattern of intrarenal RAS expression was not changed by RDN. In conclusion, RDN does not affect hypertension or the RAS in the LPK model and indicates RDN might not be a suitable antihypertensive strategy for individuals with juvenile-onset PKD.
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Renal denervation does not affect hypertension or the Renin-angiotensin system in a rodent model of juvenile-onset polycystic Kidney disease: clinical implications
'Springer Science and Business Media LLC', 2021Co-Authors: Cara M. Hildreth, Ahmed A. Rahman, Sean A. Barton, Benjamin F. Wyse, Chai K. Lim, Paul M. Pilowsky, Jacqueline K. PhillipsAbstract:Abstract We examined the effect of total and afferent renal denervation (RDN) on hypertension and the Renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic Kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and Kidney Renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; Kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P
Jan Wysocki - One of the best experts on this subject based on the ideXlab platform.
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novel variants of angiotensin converting enzyme 2 of shorter molecular size to target the Kidney Renin angiotensin system
Biomolecules, 2019Co-Authors: Jan Wysocki, Arndt Schulze, Daniel BatlleAbstract: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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abstract 099 novel angiotensin converting enzyme 2 ace2 truncates to target the Kidney Renin angiotensin system ras
Hypertension, 2019Co-Authors: Jan Wysocki, Arndt Schulze, Ming Zhao, Chad R Haney, Daniel BatlleAbstract:ACE2 is an enzyme with a molecular size of more than 100 kDa which produces Angiotensin (1-7) from Angiotensin II (1-8). Attempts to target Kidney RAS using ACE2 to treat Kidney disease are hampere...
John J Mullins - One of the best experts on this subject based on the ideXlab platform.
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proRenin contributes to angiotensin peptide formation in transgenic rats with rat proRenin expression targeted to the liver
Hypertension, 2009Co-Authors: Duncan J Campbell, Habib Karam, Joel Menard, Patrick Bruneval, John J MullinsAbstract:We reported previously that targeted expression of rat proRenin to the liver under the control of the human α1-antitrypsin promoter increased plasma proRenin levels by several-hundred–fold in male transgenic rats and caused cardiac hypertrophy, severe renal lesions, and myocardial fibrosis by 20 weeks of age, despite normal blood pressure. We examined the evolution of the phenotype of male transgenic rats over 12 months and the effects of binephrectomy on the Renin-angiotensin (Ang) system. Plasma proRenin levels were >1000-fold higher than in wild type littermates, whereas plasma and renal Ang II levels were no different from wild-type (WT) levels, and Kidney Renin levels were suppressed in transgenic rats. In contrast to our earlier report, transgenic rats had increased systolic blood pressure at 3 to 12 months of age, and only modest renal lesions and myocardial fibrosis were evident after 6 months of age. Binephrectomy reduced plasma Renin activity and concentration and proRenin levels by 50% to 80% and Ang II levels by 90% in WT rats. By contrast, binephrectomy increased plasma Renin activity and concentration and proRenin levels by 52.0-, 13.0-, and 5.8-fold, respectively, without change in Ang II levels in transgenic rats. We conclude that, in the animals studied in this report, elevated proRenin levels did not cause renal lesions or myocardial fibrosis during the first 6 months of age. Ang peptide formation consequent to the increased proRenin levels prevented reduction of Ang II levels after binephrectomy and was likely to have contributed to hypertension, cardiac hypertrophy, and suppression of Kidney Renin levels in these transgenic rats.
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Increased adrenal Renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation by cAMP, angiotensin II, and calcium
1993Co-Authors: Jorg Peters, Eberhard Hackenthal, John J Mullins, Klaus Munter, Michael Bader, Detlev GantenAbstract:The newly established rat strain TGR(mREN2)27 is a mono-genetic model in hypertension research. Microinjecting the mouse Ren-2d Renin gene caused it to become a stable part of the genome. The rats are characterized by fulminant hyperten-sion, low plasma active Renin, suppressed Kidney Renin, high plasma inactive Renin, and high extrarenal transgene expres-sion, most prominently in the adrenal cortex. Additionally, they exhibit significantly enhanced excretion of corticosteroids. Here we demonstrate that part of the plasma Renin and most of the adrenal Renin are transgene determined and that the adre-nal Renin is strongly activated. TGR(mREN2)27 adrenal cells may serve as a new tool to investigate the regulation and pro-cessing of Ren-2d-derived Renin and its significance in hyper-tension and steroid metabolism. Adrenal Renin in TGR(mREN2)27 is stimulated by 8-bromo-cAMP (8-Br-cAMP), angiotensin II (ANGII), and cal-cium. 8-Br-cAMP significantly stimulates active Renin and pro-Renin release, as well as Ren-2d mRNA. Interestingly, within 60 min 8-Br-cAMP, ANGII, and calcimycin stimulate active Renin, but not proRenin release. This indicates different intra-cellular pathways. An activated adrenal Renin-angiotensin system in TGR (mREN2)27 as well as the lack of negative feedback on Renin secretion by ANGII may be of pathophysiological significance in this hypertensive model. (J. Clin. Invest. 1993. 742-747.) Key words: ren-2d- cells * secretion * hypertension * tissue Renin-angiotensin syste
Cara M. Hildreth - One of the best experts on this subject based on the ideXlab platform.
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renal denervation does not affect hypertension or the Renin angiotensin system in a rodent model of juvenile onset polycystic Kidney disease clinical implications
Scientific Reports, 2021Co-Authors: Cara M. Hildreth, Ahmed A. Rahman, Sean A. Barton, Benjamin F. Wyse, Chai K. Lim, Paul M. Pilowsky, Jacqueline K. PhillipsAbstract:We examined the effect of total and afferent renal denervation (RDN) on hypertension and the Renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic Kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and Kidney Renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; Kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P < 0.001, n = 26). These parameters were not affected by RDN. Intrarenal mRNA expression levels of Renin, angiotensinogen, angiotensin-converting enzyme (ACE)2, and angiotensin II receptor type 1a were significantly lower, whereas ACE1 expression was significantly higher in the LPK vs. Lewis (all P < 0.05, n = 26). This pattern of intrarenal RAS expression was not changed by RDN. In conclusion, RDN does not affect hypertension or the RAS in the LPK model and indicates RDN might not be a suitable antihypertensive strategy for individuals with juvenile-onset PKD.
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Renal denervation does not affect hypertension or the Renin-angiotensin system in a rodent model of juvenile-onset polycystic Kidney disease: clinical implications
'Springer Science and Business Media LLC', 2021Co-Authors: Cara M. Hildreth, Ahmed A. Rahman, Sean A. Barton, Benjamin F. Wyse, Chai K. Lim, Paul M. Pilowsky, Jacqueline K. PhillipsAbstract:Abstract We examined the effect of total and afferent renal denervation (RDN) on hypertension and the Renin-angiotensin system (RAS) in a rodent model of juvenile-onset polycystic Kidney disease (PKD). Lewis Polycystic Kidney (LPK) and control rats received total, afferent or sham RDN by periaxonal application of phenol, capsaicin or normal saline, respectively, and were monitored for 4-weeks. Afferent RDN did not affect systolic blood pressure (SBP) determined by radiotelemetry in either strain (n = 19) while total RDN significantly reduced SBP in Lewis rats 4-weeks post-denervation (total vs. sham, 122 ± 1 vs. 130 ± 2 mmHg, P = 0.002, n = 25). Plasma and Kidney Renin content determined by radioimmunoassay were significantly lower in LPK vs. Lewis (plasma: 278.2 ± 6.7 vs. 376.5 ± 11.9 ng Ang I/ml/h; Kidney: 260.1 ± 6.3 vs. 753.2 ± 37.9 ng Ang I/mg/h, P
