Sex differences in soluble prorenin receptor in patients with type 2 diabetes.
Plasma renin activity
Sexual dimorphism
Urine angiotensinogen
Urine renin activity
eGFR
Journal
Biology of sex differences
ISSN: 2042-6410
Titre abrégé: Biol Sex Differ
Pays: England
ID NLM: 101548963
Informations de publication
Date de publication:
01 05 2021
01 05 2021
Historique:
received:
06
10
2020
accepted:
07
04
2021
entrez:
2
5
2021
pubmed:
3
5
2021
medline:
15
12
2021
Statut:
epublish
Résumé
The soluble prorenin receptor (sPRR), a member of the renin-angiotensin system (RAS), is elevated in plasma of patients with preeclampsia, hypertension, chronic kidney disease (CKD), and type 2 diabetes. Our goal was to examine the relationship between sPRR and RAS activation to define whether sexual dimorphisms in sPRR might explain sex disparities in renal outcomes in patients with type 2 diabetes. Two hundred sixty-nine participants were included in the study (mean age, 48 ± 16 years; 42% men, 58% women), including 173 controls and 96 subjects with type 2 diabetes. In plasma and urine, we measured sPRR, plasma renin activity (PRA), and prorenin. In the urine, we also measured angiotensinogen along with other biomarkers of renal dysfunction. Plasma sPRR and PRA were significantly higher in women with type 2 diabetes compared to men. In these women, plasma sPRR was positively correlated with PRA, age, and body mass index (BMI). In contrast, in men the sPRR in urine but not in plasma positively correlated with eGFR in urine, but negatively correlated with urine renin activity, plasma glucose, age, and BMI. In patients with type 2 diabetes, sPRR contributes to RAS stimulation in a sex-dependent fashion. In diabetic women, increased plasma sPRR parallels the activation of systemic RAS; while in diabetic men, decreased sPRR in urine matches intrarenal RAS stimulation. sPRR might be a potential indicator of intrarenal RAS activation and renal dysfunction in men and women with type 2 diabetes.
Sections du résumé
BACKGROUND
The soluble prorenin receptor (sPRR), a member of the renin-angiotensin system (RAS), is elevated in plasma of patients with preeclampsia, hypertension, chronic kidney disease (CKD), and type 2 diabetes. Our goal was to examine the relationship between sPRR and RAS activation to define whether sexual dimorphisms in sPRR might explain sex disparities in renal outcomes in patients with type 2 diabetes.
METHODS
Two hundred sixty-nine participants were included in the study (mean age, 48 ± 16 years; 42% men, 58% women), including 173 controls and 96 subjects with type 2 diabetes. In plasma and urine, we measured sPRR, plasma renin activity (PRA), and prorenin. In the urine, we also measured angiotensinogen along with other biomarkers of renal dysfunction.
RESULTS
Plasma sPRR and PRA were significantly higher in women with type 2 diabetes compared to men. In these women, plasma sPRR was positively correlated with PRA, age, and body mass index (BMI). In contrast, in men the sPRR in urine but not in plasma positively correlated with eGFR in urine, but negatively correlated with urine renin activity, plasma glucose, age, and BMI.
CONCLUSIONS
In patients with type 2 diabetes, sPRR contributes to RAS stimulation in a sex-dependent fashion. In diabetic women, increased plasma sPRR parallels the activation of systemic RAS; while in diabetic men, decreased sPRR in urine matches intrarenal RAS stimulation. sPRR might be a potential indicator of intrarenal RAS activation and renal dysfunction in men and women with type 2 diabetes.
Identifiants
pubmed: 33933156
doi: 10.1186/s13293-021-00374-3
pii: 10.1186/s13293-021-00374-3
pmc: PMC8088668
doi:
Substances chimiques
Receptors, Cell Surface
0
Renin
EC 3.4.23.15
Prorenin Receptor
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
33Subventions
Organisme : NIDDK NIH HHS
ID : RO1-DK114321
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107444
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD043451
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104940
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR003096
Pays : United States
Organisme : U.S. Department of Veterans Affairs
ID : #BX003725
Organisme : NIDDK NIH HHS
ID : R01 DK074970
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103337
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104375
Pays : United States
Références
Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032–45. https://doi.org/10.2215/CJN.11491116 .
pubmed: 28522654
pmcid: 5718284
Kobori H, Kamiyama M, Harrison-Bernard LM, Navar LG. Cardinal role of the intrarenal renin-angiotensin system in the pathogenesis of diabetic nephropathy. J Investig Med. 2013;61(2):256–64. https://doi.org/10.2310/JIM.0b013e31827c28bb .
pubmed: 23266706
pmcid: 3554867
Fan YY, Kobori H, Nakano D, Hitomi H, Mori H, Masaki T, et al. Aberrant activation of the intrarenal renin-angiotensin system in the developing kidneys of type 2 diabetic rats. Horm Metab Res. 2013;45(5):338–43. https://doi.org/10.1055/s-0032-1331256 .
pubmed: 23322513
pmcid: 3655199
Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet. 2014;383(9933):1973–80. https://doi.org/10.1016/S0140-6736(14)60040-4 .
pubmed: 24613026
Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J ClinInvest. 2002;109(11):1417–27.
Nabi AH, Kageshima A, Uddin MN, Nakagawa T, Park EY, Suzuki F. Binding properties of rat prorenin and renin to the recombinant rat renin/prorenin receptor prepared by a baculovirus expression system. Int J Mol Med. 2006;18(3):483–8.
pubmed: 16865234
Nurun NA, Uddin NM, Nakagawa T, Iwata H, Ichihara A, Inagami T, et al. Role of "handle" region of prorenin prosegment in the non-proteolytic activation of prorenin by binding to membrane anchored (pro)renin receptor. Front Biosci. 2007;12(12):4810–7. https://doi.org/10.2741/2429 .
pubmed: 17569611
Zhang J, Noble NA, Border WA, Owens RT, Huang Y. Receptor-dependent prorenin activation and induction of PAI-1 expression in vascular smooth muscle cells. Am J Physiol Endocrinol Metab. 2008;295(4):E810–9. https://doi.org/10.1152/ajpendo.90264.2008 .
pubmed: 18664599
pmcid: 2575903
Gonzalez AA, Zamora L, Reyes-Martinez C, Salinas-Parra N, Roldan N, Cuevas CA, et al. (Pro)renin receptor activation increases profibrotic markers and fibroblast-like phenotype through MAPK-dependent ROS formation in mouse renal collecting duct cells. Clin Exp Pharmacol Physiol. 2017;44(11):1134–44. https://doi.org/10.1111/1440-1681.12813 .
pubmed: 28696542
pmcid: 5643228
Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, Thai K, et al. The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H + -ATPase in the kidney. Hypertension. 2009;54(2):261–9. https://doi.org/10.1161/HYPERTENSIONAHA.109.128645 .
pubmed: 19546380
Gonzalez AA, Lara LS, Luffman C, Seth DM, Prieto MC. The soluble form of the prorenin receptor [s(PRR)] is augmented in the collecting ducts and in the urine of angiotensin II (Ang II)-dependent hypertensive rats. Hypertension. 2011;57(4):859–64. https://doi.org/10.1161/HYPERTENSIONAHA.110.167957 .
pubmed: 21321306
Takemitsu T, Ichihara A, Kaneshiro Y, Sakoda M, Kurauchi-Mito A, Narita T, et al. Association of (pro)renin receptor mRNA expression with angiotensin-converting enzyme mRNA expression in human artery. Am J Nephrol. 2009;30(4):361–70. https://doi.org/10.1159/000232199 .
pubmed: 19641301
Takahashi K, Yamamoto H, Hirose T, Hiraishi K, Shoji I, Shibasaki A, et al. Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. Peptides. 2010;31(7):1405–8. https://doi.org/10.1016/j.peptides.2010.04.003 .
pubmed: 20385187
Huang J, Matavelli LC, Siragy HM. Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-beta1-connective tissue growth factor signalling cascade. Clin Exp Pharmacol Physiol. 2011;38(4):215–21. https://doi.org/10.1111/j.1440-1681.2011.05486.x .
pubmed: 21265872
pmcid: 3077929
Ichihara A, Sakoda M, Mito-Kurauchi A, Itoh H. Activated prorenin as a therapeutic target for diabetic nephropathy. Diabetes Res Clin Pract. 2008;82(Supplement 1):S63–S6.
pubmed: 18922597
Cousin C, Bracquart D, Contrepas A, Corvol P, Muller L, Nguyen G. Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension. 2009;53(6):1077–82. https://doi.org/10.1161/HYPERTENSIONAHA.108.127258 .
pubmed: 19380613
Nakagawa T, Suzuki-Nakagawa C, Watanabe A, Asami E, Matsumoto M, Nakano M, et al. Site-1 protease is required for the generation of soluble (pro)renin receptor. J Biochem. 2017;161(4):369–79. https://doi.org/10.1093/jb/mvw080 .
pubmed: 28013223
Yoshikawa A, Aizaki Y, Kusano K, Kishi F, Susumu T, Iida S, et al. The (pro)renin receptor is cleaved by ADAM19 in the Golgi leading to its secretion into extracellular space. Hypertension research : official journal of the Japanese Society of Hypertension. 2011;34(5):599–605. https://doi.org/10.1038/hr.2010.284 .
Hamada K, Taniguchi Y, Shimamura Y, Inoue K, Ogata K, Ishihara M, et al. Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease. Clin Exp Nephrol. 2013;17(6):848–56. https://doi.org/10.1007/s10157-013-0803-y .
pubmed: 23564382
Nishijima T, Tajima K, Takahashi K, Sakurai S. Elevated plasma levels of soluble (pro)renin receptor in patients with obstructive sleep apnea syndrome: association with polysomnographic parameters. Peptides. 2014;56:14–21. https://doi.org/10.1016/j.peptides.2014.03.008 .
pubmed: 24657284
Thomason J, Reyes M, Allen SR, Jones RO, Beeram MR, Kuehl TJ, et al. Elevation of (pro)renin and (pro)renin receptor in preeclampsia. Am J Hypertens. 2015;28(10):1277–84. https://doi.org/10.1093/ajh/hpv019 .
pubmed: 25767135
Morimoto S, Ando T, Niiyama M, Seki Y, Yoshida N, Watanabe D, et al. Serum soluble (pro)renin receptor levels in patients with essential hypertension. Hypertension research : official journal of the Japanese Society of Hypertension. 2014;37(7):642–8. https://doi.org/10.1038/hr.2014.46 .
Deinum J, Rønn B, Mathiesen E, Derkx FH, Hop WC, Schalekamp MA. Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus. Diabetologia. 1999;42(8):1006–10. https://doi.org/10.1007/s001250051260 .
pubmed: 10491762
Davies L, Fulcher GR, Atkins A, Frumar K, Monaghan J, Stokes G, et al. The relationship of prorenin values to microvascular complications in patients with insulin-dependent diabetes mellitus. J Diabetes Complications. 1999;13(1):45–51. https://doi.org/10.1016/S1056-8727(98)00020-8 .
pubmed: 10232709
Luetscher JA, Kraemer FB, Wilson DM, Schwartz HC, Bryer-Ash M. Increased plasma inactive renin in diabetes mellitus. A marker of microvascular complications. N Engl J Med. 1985;312(22):1412–7. https://doi.org/10.1056/NEJM198505303122202 .
pubmed: 3887168
Nguyen G, Blanchard A, Curis E, Bergerot D, Chambon Y, Hirose T, et al. Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity. Hypertension. 2014;63(2):297–302. https://doi.org/10.1161/HYPERTENSIONAHA.113.02217 .
pubmed: 24218434
Mauvais-Jarvis F, Manson JE, Stevenson JC, Fonseca VA. Menopausal hormone therapy and type 2 diabetes prevention: evidence, mechanisms, and clinical implications. Endocr Rev. 2017;38(3):173–88. https://doi.org/10.1210/er.2016-1146 .
pubmed: 28323934
pmcid: 5460681
Colafella KMM, Denton KM. Sex-specific differences in hypertension and associated cardiovascular disease. Nat Rev Nephrol. 2018;14(3):185–201. https://doi.org/10.1038/nrneph.2017.189 .
pubmed: 29380817
Shepard BD. Sex differences in diabetes and kidney disease: mechanisms and consequences. Am J Physiol Renal Physiol. 2019;317(2):F456–F62. https://doi.org/10.1152/ajprenal.00249.2019 .
pubmed: 31241989
pmcid: 6732459
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130(6):461–70. https://doi.org/10.7326/0003-4819-130-6-199903160-00002 .
pubmed: 10075613
Mills KT, Kobori H, Hamm LL, Alper AB, Khan IE, Rahman M, et al. Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease. Nephrol Dial Transplant. 2012;27(8):3176–81. https://doi.org/10.1093/ndt/gfs011 .
pubmed: 22399491
pmcid: 3408937
Du T, Fernandez C, Barshop R, Guo Y, Krousel-Wood M, Chen W, et al. Sex differences in cardiovascular risk profile from childhood to midlife between individuals who did and did not develop diabetes at follow-up: the bogalusa heart study. Diabetes Care. 2019;42(4):635–43. https://doi.org/10.2337/dc18-2029 .
pubmed: 30692238
pmcid: 6429632
Dong WH, Chen JC, He YL, Xu JJ, Mei YA. Resveratrol inhibits K(v)2.2 currents through the estrogen receptor GPR30-mediated PKC pathway. Am J Physiol Cell Physiol. 2013;305(5):C547–57. https://doi.org/10.1152/ajpcell.00146.2013 .
pubmed: 23804203
Kim EN, Kim MY, Lim JH, Kim Y, Shin SJ, Park CW, et al. The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system. Atherosclerosis. 2018;270:123–31. https://doi.org/10.1016/j.atherosclerosis.2018.01.043 .
pubmed: 29407880
Binger KJ, Muller DN. Autophagy and the (pro)renin receptor. Front Endocrinol (Lausanne). 2013;4:155. https://doi.org/10.3389/fendo.2013.00155 .
Watanabe N, Morimoto S, Fujiwara T, Suzuki T, Taniguchi K, Mori F, et al. Prediction of gestational diabetes mellitus by soluble (pro)renin receptor during the first trimester. J Clin Endocrinol Metab. 2013;98(6):2528–35. https://doi.org/10.1210/jc.2012-4139 .
pubmed: 23720787
Barsha G, Denton KM, Mirabito Colafella KM. Sex- and age-related differences in arterial pressure and albuminuria in mice. Biol Sex Differ. 2016;7(1):57. https://doi.org/10.1186/s13293-016-0110-x .
pubmed: 27895890
pmcid: 5109725
Deinum J, Tarnow L, van Gool JM, de Bruin RA, Derkx FH, Schalekamp MA, et al. Plasma renin and prorenin and renin gene variation in patients with insulin-dependent diabetes mellitus and nephropathy. Nephrol DialTransplant. 1999;14(8):1904–11. https://doi.org/10.1093/ndt/14.8.1904 .
Danser AH, Derkx FH, Schalekamp MA, Hense HW, Riegger GA, Schunkert H. Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans. J Hypertens. 1998;16(6):853–62. https://doi.org/10.1097/00004872-199816060-00017 .
pubmed: 9663926
Danser AH. The role of the (pro)renin receptor in hypertensive disease. Am J Hypertens. 2015;28(10):1187–96. https://doi.org/10.1093/ajh/hpv045 .
pubmed: 25890829
Sautin YY, Lu M, Gaugler A, Zhang L, Gluck SL. Phosphatidylinositol 3-kinase-mediated effects of glucose on vacuolar H+-ATPase assembly, translocation, and acidification of intracellular compartments in renal epithelial cells. Mol Cell Biol. 2005;25(2):575–89. https://doi.org/10.1128/MCB.25.2.575-589.2005 .
pubmed: 15632060
pmcid: 543406
Sato H, Iwano M, Akai Y, Kurioka H, Kubo A, Yamaguchi T, et al. Increased excretion of urinary transforming growth factor beta 1 in patients with diabetic nephropathy. Am J Nephrol. 1998;18(6):490–4. https://doi.org/10.1159/000013415 .
pubmed: 9845822
Shaker YM, Soliman HA, Ezzat E, Hussein NS, Ashour E, Donia A, et al. Serum and urinary transforming growth factor beta 1 as biochemical markers in diabetic nephropathy patients. Beni-Suef Univ J Basic Appl Sci. 2014;3(1):16–23. https://doi.org/10.1016/j.bjbas.2014.02.002 .
Kang JJ, Toma I, Sipos A, Meer EJ, Vargas SL, Peti-Peterdi J. The collecting duct is the major source of prorenin in diabetes. Hypertension. 2008;51(6):1597–604. https://doi.org/10.1161/HYPERTENSIONAHA.107.107268 .
pubmed: 18413493
Ichihara A, Sakoda M, Kurauchi-Mito A, Nishiyama A, Itoh H. Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. J Am Soc Hypertension. 2009;2(5):332–40.
Prieto MC, Reverte V, Mamenko M, Kuczeriszka M, Veiras LC, Rosales CB, et al. Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice. Am J Physiol Renal Physiol. 2017;313(6):F1243–F53. https://doi.org/10.1152/ajprenal.00152.2017 .
pubmed: 28814438
pmcid: 5814641
van den Heuvel M, Batenburg WW, Jainandunsing S, Garrelds IM, van Gool JM, Feelders RA, et al. Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney. J Hypertens. 2011;29(11):2147–55. https://doi.org/10.1097/HJH.0b013e32834bbcbf .
pubmed: 21941204
Tang J, Wysocki J, Ye M, Valles PG, Rein J, Shirazi M, et al. Urinary renin in patients and mice with diabetic kidney disease. Hypertension. 2019;74(1):83–94. https://doi.org/10.1161/HYPERTENSIONAHA.119.12873 .
pubmed: 31079532
Tojo A, Kinugasa S, Fujita T, Wilcox CS. A local renal renin-angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats. Diabetes Metab Syndr Obes. 2016;9:1–10. https://doi.org/10.2147/DMSO.S91245 .
pubmed: 26848273
pmcid: 4723098
Sun Y, Lu X, Danser AHJ. Megalin: a novel determinant of renin-angiotensin system activity in the kidney? Curr Hypertens Rep. 2020;22(4):30. https://doi.org/10.1007/s11906-020-01037-1 .
pubmed: 32172431
pmcid: 7072043
Roksnoer LC, Heijnen BF, Nakano D, Peti-Peterdi J, Walsh SB, Garrelds IM, et al. On the origin of urinary renin: a translational approach. Hypertension. 2016;67(5):927–33. https://doi.org/10.1161/HYPERTENSIONAHA.115.07012 .
pubmed: 26928805
Roksnoer LC, Verdonk K, Garrelds IM, van Gool JM, Zietse R, Hoorn EJ, et al. Methodologic issues in the measurement of urinary renin. Clin J Am Soc Nephrol. 2014;9(7):1163–7. https://doi.org/10.2215/CJN.12661213 .
pubmed: 24742480
pmcid: 4078972
Schuh CD, Polesel M, Platonova E, Haenni D, Gassama A, Tokonami N, et al. Combined structural and functional imaging of the kidney reveals major axial differences in proximal tubule endocytosis. J Am Soc Nephrol. 2018;29(11):2696–712. https://doi.org/10.1681/ASN.2018050522 .
pubmed: 30301861
pmcid: 6218873
Maranon R, Reckelhoff JF. Sex and gender differences in control of blood pressure. Clin Sci (Lond). 2013;125(7):311–8. https://doi.org/10.1042/CS20130140 .
pubmed: 23746374
pmcid: 4283814
Tamargo J, Rosano G, Walther T, Duarte J, Niessner A, Kaski JC, et al. Gender differences in the effects of cardiovascular drugs. Eur Heart J Cardiovasc Pharmacother. 2017;3(3):163–82. https://doi.org/10.1093/ehjcvp/pvw042 .
pubmed: 28329228
Leete J, Gurley S, Layton A. Modeling sex differences in the renin angiotensin system and the efficacy of antihypertensive therapies. Comput Chem Eng. 2018;112:253–64. https://doi.org/10.1016/j.compchemeng.2018.02.009 .
pubmed: 30555192
pmcid: 6290907
Leete J, Layton AT. Sex-specific long-term blood pressure regulation: modeling and analysis. Comput Biol Med. 2018;104:139–48. https://doi.org/10.1016/j.compbiomed.2018.11.002 .
pubmed: 30472496
pmcid: 6590082
Woods TC, Satou R, Miyata K, Katsurada A, Dugas CM, Klingenberg NC, et al. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol. 2019;49(4):331–42. https://doi.org/10.1159/000499597 .
pubmed: 30921791
Yoshimoto T, Furuki T, Kobori H, Miyakawa M, Imachi H, Murao K, et al. Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. J Investig Med. 2017;65(7):1057–61. https://doi.org/10.1136/jim-2017-000445 .
pubmed: 28596160
pmcid: 5812257
Narumi K, Sato E, Hirose T, Yamamoto T, Nakamichi T, Miyazaki M, et al. (Pro)renin receptor is involved in mesangial fibrosis and matrix expansion. Sci Rep. 2018;8(1):16. https://doi.org/10.1038/s41598-017-18314-w .
pubmed: 29311647
pmcid: 5758707
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–60. https://doi.org/10.1056/NEJMoa011303 .
pubmed: 11565517
Wang F, Luo R, Zou CJ, Xie S, Peng K, Zhao L, et al. Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARgamma. JCI Insight. 2020;5(7):7. https://doi.org/10.1172/jci.insight.128061 .