Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes
Sridevi Gutta, Nadja Grobe, Meenasri Kumbaji, Hassan Osman, Mohammad Saklayen, Gengxin Li, Khalid M Elased, Sridevi Gutta, Nadja Grobe, Meenasri Kumbaji, Hassan Osman, Mohammad Saklayen, Gengxin Li, Khalid M Elased
Abstract
Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.
Keywords: ACE2; ADAM17; NEP; chronic kidney disease; diabetic nephropathy; type 2 diabetes.
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References
- Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol 265: F477–F486, 1993. doi:10.1152/ajprenal.1993.265.4.F477.
- Bae EH, Fang F, Williams VR, Konvalinka A, Zhou X, Patel VB, Song X, John R, Oudit GY, Pei Y, Scholey JW. Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome. Kidney Int 91: 1347–1361, 2017. doi:10.1016/j.kint.2016.12.022.
- Bayés-Genís A, Barallat J, Galán A, de Antonio M, Domingo M, Zamora E, Urrutia A, Lupón J. Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients. J Am Coll Cardiol 65: 657–665, 2015. doi:10.1016/j.jacc.2014.11.048.
- Brosius FC, Pennathur S. How to find a prognostic biomarker for progressive diabetic nephropathy. Kidney Int 83: 996–998, 2013. doi:10.1038/ki.2013.58.
- Burns KD, Lytvyn Y, Mahmud FH, Daneman D, Deda L, Dunger DB, Deanfield J, Dalton RN, Elia Y, Har R, Van JAD, Bradley TJ, Slorach C, Hui W, Xiao F, Zimpelmann J, Mertens L, Moineddin R, Reich HN, Sochett E, Scholey JW, Cherney DZI. The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes. Am J Physiol Renal Physiol 312: F335–F342, 2017. doi:10.1152/ajprenal.00438.2016.
- Casarini DE, Plavinik FL, Zanella MT, Marson O, Krieger JE, Hirata IY, Stella RCR. Angiotensin converting enzymes from human urine of mild hypertensive untreated patients resemble the N-terminal fragment of human angiotensin I-converting enzyme. Int J Biochem Cell Biol 33: 75–85, 2001. doi:10.1016/S1357-2725(00)00072-8.
- Cherney DZI, Xiao F, Zimpelmann J, Har RLH, Lai V, Scholey JW, Reich HN, Burns KD. Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes. Can J Physiol Pharmacol 92: 703–706, 2014. doi:10.1139/cjpp-2014-0065.
- Chodavarapu H, Grobe N, Somineni HK, Salem ESB, Madhu M, Elased KM. Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. PLoS One 8: e62833, 2013. doi:10.1371/journal.pone.0062833.
- Collins AJ, Couser WG, Dirks JH, Kopple JD, Reiser T, Riella MC, Robinson S, Shah SV, Wilson A. World Kidney Day: an idea whose time has come. Natl Med J India 19: 55–57, 2006.
- Domenig O, Manzel A, Grobe N, Königshausen E, Kaltenecker CC, Kovarik JJ, Stegbauer J, Gurley SB, van Oyen D, Antlanger M, Bader M, Motta-Santos D, Santos RA, Elased KM, Säemann MD, Linker RA, Poglitsch M. Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney. Sci Rep 6: 33678, 2016. doi:10.1038/srep33678.
- Dunkler D, Gao P, Lee SF, Heinze G, Clase CM, Tobe S, Teo KK, Gerstein H, Mann JFE, Oberbauer R; ONTARGET and ORIGIN Investigators . Risk prediction for early CKD in type 2 diabetes. Clin J Am Soc Nephrol 10: 1371–1379, 2015. doi:10.2215/CJN.10321014.
- Erdös EG, Skidgel RA . Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J 3: 145–151, 1989. doi:10.1096/fasebj.3.2.2521610.
- Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens 28: 15–21, 2015. doi:10.1093/ajh/hpu086.
- Giorgino F, Laviola L, Cavallo Perin P, Solnica B, Fuller J, Chaturvedi N. Factors associated with progression to macroalbuminuria in microalbuminuric type 1 diabetic patients: the EURODIAB Prospective Complications Study. Diabetologia 47: 1020–1028, 2004. doi:10.1007/s00125-004-1413-8.
- Grobe N, Elased KM, Cool DR, Morris M. Mass spectrometry for the molecular imaging of angiotensin metabolism in kidney. Am J Physiol Endocrinol Metab 302: E1016–E1024, 2012. doi:10.1152/ajpendo.00515.2011.
- Grobe N, Di Fulvio M, Kashkari N, Chodavarapu H, Somineni HK, Singh R, Elased KM. Functional and molecular evidence for expression of the renin angiotensin system and ADAM17-mediated ACE2 shedding in COS7 cells. Am J Physiol Cell Physiol 308: C767–C777, 2015. doi:10.1152/ajpcell.00247.2014.
- Guan H, Liu Y, Daily A, Police S, Kim M-H, Oddo S, LaFerla FM, Pauly JR, Murphy MP, Hersh LB. Peripherally expressed neprilysin reduces brain amyloid burden: a novel approach for treating Alzheimer’s disease. J Neurosci Res 87: 1462–1473, 2009. doi:10.1002/jnr.21944.
- Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63: 713–735, 2014. doi:10.1053/j.ajkd.2014.01.416.
- Jensen JS, Borch-Johnsen K, Deckert T, Deckert M, Jensen G, Feldt-Rasmussen B. Reduced glomerular size- and charge-selectivity in clinically healthy individuals with microalbuminuria. Eur J Clin Invest 25: 608–614, 1995. doi:10.1111/j.1365-2362.1995.tb01753.x.
- Juretzko A, Steinbach A, Hannemann A, Endlich K, Endlich N, Friedrich N, Lendeckel U, Stracke S, Rettig R. Urinary angiotensinogen and renin excretion are associated with chronic kidney disease. Kidney Blood Press Res 42: 145–155, 2017. doi:10.1159/000474932.
- Kamiyama M, Zsombok A, Kobori H. Urinary angiotensinogen as a novel early biomarker of intrarenal renin-angiotensin system activation in experimental type 1 diabetes. J Pharmacol Sci 119: 314–323, 2012. doi:10.1254/jphs.12076FP.
- Krolewski AS, Niewczas MA, Skupien J, Gohda T, Smiles A, Eckfeldt JH, Doria A, Warram JH. Early progressive renal decline precedes the onset of microalbuminuria and its progression to macroalbuminuria. Diabetes Care 37: 226–234, 2014. doi:10.2337/dc13-0985.
- Kuruppu S, Rajapakse NW, Minond D, Smith AI. Production of soluble Neprilysin by endothelial cells. Biochem Biophys Res Commun 446: 423–427, 2014. doi:10.1016/j.bbrc.2014.01.158.
- Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, Hooper NM, Turner AJ. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 280: 30113–30119, 2005. doi:10.1074/jbc.M505111200.
- Lely AT, Hamming I, van Goor H, Navis GJ. Renal ACE2 expression in human kidney disease. J Pathol 204: 587–593, 2004. doi:10.1002/path.1670.
- Lew RA, Warner FJ, Hanchapola I, Yarski MA, Ramchand J, Burrell LM, Smith AI. Angiotensin-converting enzyme 2 catalytic activity in human plasma is masked by an endogenous inhibitor. Exp Physiol 93: 685–693, 2008. doi:10.1113/expphysiol.2007.040352.
- Lew RA, Warner FJ, Hanchapola I, Smith AI. Characterization of angiotensin converting enzyme-2 (ACE2) in human urine. Int J Pept Res Ther 12: 283–289, 2006. doi:10.1007/s10989-006-9031-6.
- Liang Y, Deng H, Bi S, Cui Z, A L, Zheng D, Wang Y. Urinary angiotensin converting enzyme 2 increases in patients with type 2 diabetic mellitus. Kidney Blood Press Res 40: 101–110, 2015. doi:10.1159/000368486.
- Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, He J, Lash J, Lustigova E, Rosas SE, Simonson MS, Tao K, Hsu CY; Chronic Renal Insufficiency Cohort (CRIC) study investigators . Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney Int 83: 909–914, 2013. doi:10.1038/ki.2012.458.
- Maguer-Satta V, Besançon R, Bachelard-Cascales E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. Stem Cells 29: 389–396, 2011. doi:10.1002/stem.592.
- McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees . Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371: 993–1004, 2014. doi:10.1056/NEJMoa1409077.
- Mizuiri S, Aoki T, Hemmi H, Arita M, Sakai K, Aikawa A. Urinary angiotensin-converting enzyme 2 in patients with CKD. Nephrology (Carlton) 16: 567–572, 2011. doi:10.1111/j.1440-1797.2011.01467.x.
- Pajenda S, Mechtler K, Wagner L. Urinary neprilysin in the critically ill patient. BMC Nephrol 18: 172, 2017. doi:10.1186/s12882-017-0587-5.
- Park SE, Kim WJ, Park SW, Park JW, Lee N, Park CY, Youn BS. High urinary ACE2 concentrations are associated with severity of glucose intolerance and microalbuminuria. Eur J Endocrinol 168: 203–210, 2013. doi:10.1530/EJE-12-0782.
- Parvanova AI, Trevisan R, Iliev IP, Dimitrov BD, Vedovato M, Tiengo A, Remuzzi G, Ruggenenti P. Insulin resistance and microalbuminuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion. Diabetes 55: 1456–1462, 2006. doi:10.2337/db05-1484.
- Patel VB, Clarke N, Wang Z, Fan D, Parajuli N, Basu R, Putko B, Kassiri Z, Turner AJ, Oudit GY. Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol 66: 167–176, 2014. doi:10.1016/j.yjmcc.2013.11.017.
- Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, Krolewski AS. Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol 18: 1353–1361, 2007. doi:10.1681/ASN.2006080872.
- Riera M, Anguiano L, Clotet S, Roca-Ho H, Rebull M, Pascual J, Soler MJ. Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria. Am J Physiol Renal Physiol 310: F534–F546, 2016. doi:10.1152/ajprenal.00082.2015.
- Roberts MA, Velkoska E, Ierino FL, Burrell LM. Angiotensin-converting enzyme 2 activity in patients with chronic kidney disease. Nephrol Dial Transplant 28: 2287–2294, 2013. doi:10.1093/ndt/gft038.
- Ruggenenti P, Ruggiero B, Cravedi P, Vivarelli M, Massella L, Marasà M, Chianca A, Rubis N, Ene-Iordache B, Rudnicki M, Pollastro RM, Capasso G, Pisani A, Pennesi M, Emma F, Remuzzi G; Rituximab in Nephrotic Syndrome of Steroid-Dependent or Frequently Relapsing Minimal Change Disease Or Focal Segmental Glomerulosclerosis (NEMO) Study Group . Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 25: 850–863, 2014. doi:10.1681/ASN.2013030251.
- Salem ESB, Grobe N, Elased KM. Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice. Am J Physiol Renal Physiol 306: F629–F639, 2014. doi:10.1152/ajprenal.00516.2013.
- Salih M, Bovee DM, Roksnoer LCW, Casteleijn NF, Bakker SJL, Gansevoort RT, Zietse R, Danser AHJ, Hoorn EJ. Urinary renin-angiotensin markers in polycystic kidney disease. Am J Physiol Renal Physiol 313: F874–F881, 2017. doi:10.1152/ajprenal.00209.2017.
- Skidgel RA, Schulz WW, Tam LT, Erdös EG. Human renal angiotensin I converting enzyme and neutral endopeptidase. Kidney Int Suppl 20: S45–S48, 1987.
- Somineni HK, Boivin GP, Elased KM. Daily exercise training protects against albuminuria and angiotensin converting enzyme 2 shedding in db/db diabetic mice. J Endocrinol 221: 235–251, 2014. doi:10.1530/JOE-13-0532.
- Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop P-H; FinnDiane Study Group . Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens 30: 375–383, 2012. doi:10.1097/HJH.0b013e32834f04b6.
- Standeven KF, Hess K, Carter AM, Rice GI, Cordell PA, Balmforth AJ, Lu B, Scott DJ, Turner AJ, Hooper NM, Grant PJ. Neprilysin, obesity and the metabolic syndrome. Int J Obes 35: 1031–1040, 2011. doi:10.1038/ijo.2010.227.
- Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275: 33238–33243, 2000. doi:10.1074/jbc.M002615200.
- Warner FJ, Lew RA, Smith AI, Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem 280: 39353–39362, 2005. doi:10.1074/jbc.M508914200.
- Wysocki J, Goodling A, Burgaya M, Whitlock K, Ruzinski J, Batlle D, Afkarian M. Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease. Am J Physiol Renal Physiol 313: F487–F494, 2017. doi:10.1152/ajprenal.00074.2017.
- Wysocki J, Ye M, Khattab AM, Fogo A, Martin A, David NV, Kanwar Y, Osborn M, Batlle D. Angiotensin-converting enzyme 2 amplification limited to the circulation does not protect mice from development of diabetic nephropathy. Kidney Int, 91: 1336–1346, 2017. doi:10.1016/j.kint.2016.09.032.
- Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, Coffman TM, Chen S, Batlle D. ACE and ACE2 activity in diabetic mice. Diabetes 55: 2132–2139, 2006. doi:10.2337/db06-0033.
- Xiao F, Hiremath S, Knoll G, Zimpelmann J, Srivaratharajah K, Jadhav D, Fergusson D, Kennedy CRJ, Burns KD. Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes. PLoS One 7: e37649, 2012. doi:10.1371/journal.pone.0037649.
- Xiao F, Zimpelmann J, Agaybi S, Gurley SB, Puente L, Burns KD. Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells. PLoS One 9: e85958, 2014. doi:10.1371/journal.pone.0085958.
- Xu J, Sriramula S, Xia H, Moreno-Walton L, Culicchia F, Domenig O, Poglitsch M, Lazartigues E. Clinical relevance and role of neuronal AT1 receptors in ADAM17-Mediated ACE2 shedding in neurogenic hypertension. Circ Res 121: 43–55, 2017. doi:10.1161/CIRCRESAHA.116.310509.
- Yamaleyeva LM, Gilliam-Davis S, Almeida I, Brosnihan KB, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Renal Physiol 302: F1374–F1384, 2012. doi:10.1152/ajprenal.00656.2011.
- Yang X, Chen C, Tian J, Zha Y, Xiong Y, Sun Z, Chen P, Li J, Yang T, Ma C, Liu H, Wang X, Hou FF. Urinary angiotensinogen level predicts AKI in acute decompensated heart failure: a prospective, two-stage study. J Am Soc Nephrol 26: 2032–2041, 2015. doi:10.1681/ASN.2014040408.
- Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol 17: 3067–3075, 2006. doi:10.1681/ASN.2006050423.
- Zraika S, Koh DS, Barrow BM, Lu B, Kahn SE, Andrikopoulos S. Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx. Diabetes 62: 1593–1601, 2013. doi:10.2337/db11-1593.
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