Skip to content
2000
image of Predictive Value and Potential of Targeting Complement Factor C3 in Patients with Renal Injury in Preeclampsia

Abstract

Aim

The activation of the complement system is accompanied by the occurrence and development of preeclampsia, as well as kidney diseases. Here, the role of complement C3 [C3] in renal injury in preeclampsia was explored, and its potential application as an early diagnostic biomarker or drug target to ameliorate kidney injury induced by preeclampsia was preliminarily evaluated.

Method

A total of 48 subjects were included in the present study, and the complement C3 levels and renal function were analyzed.

Results

Patients with preeclampsia with severe features [sPe] had poorer renal function compared with the patients with preeclampsia. Urinary C3 levels could be used to distinguish between healthy controls, patients with preeclampsia, and patients with sPe. Increased renal inflammation and oxidative stress were notably increased in the preeclampsia mice with impaired renal function and attenuation of C3 activity using a C3 receptor antagonist, which reduced Pe-like symptoms and renal impairment, decreased serum blood urea nitrogen, creatinine, and urinary albumin levels, and decreased expression of the oxidative stress marker malondialdehyde, whilst increasing superoxide dismutase activity. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 ([HO-1) pathway was involved in the inhibition of complement C3 in the kidney.

Conclusion

Higher urinary C3 levels could be used to predict kidney damage in preeclampsia, and inhibition of C3 activity might ameliorate the renal impairment in preeclampsia through activation of Nrf2/HO-1 pathway.

Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240302343240801105324
2025-01-06
2025-06-23
Loading full text...

Full text loading...

References

  1. Vyas V. Goyal A. Acute Pulmonary Embolism. StatPearls Treasure Island StatPearls Publishing 2023
    [Google Scholar]
  2. Tomimatsu T. Mimura K. Endo M. Kumasawa K. Kimura T. Pathophysiology of preeclampsia: an angiogenic imbalance and long-lasting systemic vascular dysfunction. Hypertens. Res. 2017 40 4 305 310 10.1038/hr.2016.152 27829661
    [Google Scholar]
  3. Phipps E.A. Thadhani R. Benzing T. Karumanchi S.A. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat. Rev. Nephrol. 2019 15 5 275 289 10.1038/s41581‑019‑0119‑6 30792480
    [Google Scholar]
  4. Rana S. Burke S.D. Karumanchi S.A. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am. J. Obstet. Gynecol. 2022 226 2 Suppl. S1019 S1034 10.1016/j.ajog.2020.10.022 33096092
    [Google Scholar]
  5. Zhang Y. Li Z. Wu H. Wang J. Zhang S. Esculetin alleviates murine lupus nephritis by inhibiting complement activation and enhancing Nrf2 signaling pathway. J. Ethnopharmacol. 2022 288 115004 10.1016/j.jep.2022.115004 35051603
    [Google Scholar]
  6. Wang W. Sheng L. Chen Y. Li Z. Wu H. Ma J. Zhang D. Chen X. Zhang S. Total coumarin derivates from Hydrangea paniculata attenuate renal injuries in cationized-BSA induced membranous nephropathy by inhibiting complement activation and interleukin 10-mediated interstitial fibrosis. Phytomedicine 2022 96 153886 10.1016/j.phymed.2021.153886 35026512
    [Google Scholar]
  7. Reis ES. Mastellos DC. Hajishengallis G. Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019 19 8 503 516 10.1038/s41577‑019‑0168‑x
    [Google Scholar]
  8. Pierik E. Prins J.R. van Goor H. Dekker G.A. Daha M.R. Seelen M.A.J. Scherjon S.A. Dysregulation of Complement Activation and Placental Dysfunction: A Potential Target to Treat Preeclampsia? Front. Immunol. 2020 10 3098 10.3389/fimmu.2019.03098 32010144
    [Google Scholar]
  9. Burwick R.M. Feinberg B.B. Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Am. J. Obstet. Gynecol. 2022 226 2 S1059 S1070 10.1016/j.ajog.2020.09.038 32986992
    [Google Scholar]
  10. Regal J.F. Burwick R.M. Fleming S.D. The Complement System and Preeclampsia. Curr. Hypertens. Rep. 2017 19 11 87 10.1007/s11906‑017‑0784‑4 29046976
    [Google Scholar]
  11. Girardi G. Lingo J.J. Fleming S.D. Regal J.F. Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond. Front. Immunol. 2020 11 1681 10.3389/fimmu.2020.01681 32849586
    [Google Scholar]
  12. Wu M. Jia B. Li M. Complement C3 and Activated Fragment C3a Are Involved in Complement Activation and Anti-Bacterial Immunity. Front. Immunol. 2022 13 813173 10.3389/fimmu.2022.813173 35281048
    [Google Scholar]
  13. Blakey H. Sun R. Xie L. Russell R. Sarween N. Hodson J. Hargitai B. Marton T. A H Neil D. Wong E. Sheerin N.S. Bramham K. Harris C.L. Knox E. Drayson M. Lipkin G. Pre-eclampsia is associated with complement pathway activation in the maternal and fetal circulation, and placental tissue. Pregnancy Hypertens. 2023 32 43 49 10.1016/j.preghy.2023.04.001 37088032
    [Google Scholar]
  14. Lokki A.I. Kaartokallio T. Holmberg V. Onkamo P. Koskinen L.L.E. Saavalainen P. Heinonen S. Kajantie E. Kere J. Kivinen K. Pouta A. Villa P.M. Hiltunen L. Laivuori H. Meri S. Analysis of Complement C3 Gene Reveals Susceptibility to Severe Preeclampsia. Front. Immunol. 2017 8 589 10.3389/fimmu.2017.00589 28611769
    [Google Scholar]
  15. Sarween N. Drayson M.T. Hodson J. Knox E.M. Plant T. Day C.J. Lipkin G.W. Humoral immunity in late‐onset Pre‐eclampsia and linkage with angiogenic and inflammatory markers. Am. J. Reprod. Immunol. 2018 80 5 e13041 10.1111/aji.13041 30168226
    [Google Scholar]
  16. Lillegard K.E. Loeks-Johnson A.C. Opacich J.W. Peterson J.M. Bauer A.J. Elmquist B.J. Regal R.R. Gilbert J.S. Regal J.F. Differential effects of complement activation products c3a and c5a on cardiovascular function in hypertensive pregnant rats. J. Pharmacol. Exp. Ther. 2014 351 2 344 351 10.1124/jpet.114.218123 25150279
    [Google Scholar]
  17. Chen L. Fukuda N. Matsumoto T. Abe M. Role of complement 3 in the pathogenesis of hypertension. Hypertens Res. 2020 43 4 255 262 10.1038/s41440‑019‑0371‑y
    [Google Scholar]
  18. Chen L. Fukuda N. Shimizu S. Kobayashi H. Tanaka S. Nakamura Y. Matsumoto T. Abe M. Role of complement 3 in renin generation during the differentiation of mesenchymal stem cells to smooth muscle cells. Am. J. Physiol. Cell Physiol. 2020 318 5 C981 C990 10.1152/ajpcell.00461.2019 32208992
    [Google Scholar]
  19. Merle N.S. Grunenwald A. Rajaratnam H. Gnemmi V. Frimat M. Figueres M.L. Knockaert S. Bouzekri S. Charue D. Noe R. Robe-Rybkine T. Le-Hoang M. Brinkman N. Gentinetta T. Edler M. Petrillo S. Tolosano E. Miescher S. Le Jeune S. Houillier P. Chauvet S. Rabant M. Dimitrov J.D. Fremeaux-Bacchi V. Blanc-Brude O.P. Roumenina L.T. Intravascular hemolysis activates complement via cell-free heme and heme-loaded microvesicles. JCI Insight 2018 3 12 e96910 10.1172/jci.insight.96910 29925688
    [Google Scholar]
  20. Timmermans S.A.M.E.G. Abdul-Hamid M.A. Potjewijd J. Theunissen R.O.M.F.I.H. Damoiseaux J.G.M.C. Reutelingsperger C.P. van Paassen P. C5b9 Formation on Endothelial Cells Reflects Complement Defects among Patients with Renal Thrombotic Microangiopathy and Severe Hypertension. J. Am. Soc. Nephrol. 2018 29 8 2234 2243 10.1681/ASN.2018020184 29858281
    [Google Scholar]
  21. Cook H.T. Evolving complexity of complement-related diseases. Curr. Opin. Nephrol. Hypertens. 2018 27 3 165 170 10.1097/MNH.0000000000000412 29517501
    [Google Scholar]
  22. Omatsu K. Kobayashi T. Murakami Y. Suzuki M. Ohashi R. Sugimura M. Kanayama N. Phosphatidylserine/phosphatidylcholine microvesicles can induce preeclampsia-like changes in pregnant mice. Semin. Thromb. Hemost. 2005 31 3 314 320 10.1055/s‑2005‑872438 16052403
    [Google Scholar]
  23. Chinese Guidelines for the Diagnosis and Treatment of Pregnancy Induced Hypertension (2015). Zhonghua Fu Chan Ke Za Zhi 2015 50 10 721 728 26675569
    [Google Scholar]
  24. Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China(2020). Zhonghua Fu Chan Ke Za Zhi 2020 55 4 227 238 32375429
    [Google Scholar]
  25. Mező B. Heilos A. Böhmig G.A. Eskandary F. Wahrmann M. Bond G. Kozakowski N. Halloran P.F. Rusai K. Prohászka Z. Complement markers in blood and urine: no diagnostic value in late silent antibody-mediated rejection. Transplant. Direct 2019 5 7 e470 10.1097/TXD.0000000000000915 31334344
    [Google Scholar]
  26. Ma R. Cui Z. Liao Y. Zhao M. Complement activation contributes to the injury and outcome of kidney in human anti-glomerular basement membrane disease. J. Clin. Immunol. 2013 33 1 172 178 10.1007/s10875‑012‑9772‑2 22941511
    [Google Scholar]
  27. Waker C.A. Kaufman M.R. Brown T.L. Current state of preeclampsia mouse models: approaches, relevance, and standardization. Front. Physiol. 2021 12 681632 10.3389/fphys.2021.681632 34276401
    [Google Scholar]
  28. Ames R.S. Lee D. Foley J.J. Jurewicz A.J. Tornetta M.A. Bautsch W. Settmacher B. Klos A. Erhard K.F. Cousins R.D. Sulpizio A.C. Hieble J.P. McCafferty G. Ward K.W. Adams J.L. Bondinell W.E. Underwood D.C. Osborn R.R. Badger A.M. Sarau H.M. Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. J. Immunol. 2001 166 10 6341 6348 10.4049/jimmunol.166.10.6341 11342658
    [Google Scholar]
  29. Taguchi S. Azushima K. Yamaji T. Urate S. Suzuki T. Abe E. Tanaka S. Tsukamoto S. Kamimura D. Kinguchi S. Yamashita A. Wakui H. Tamura K. Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy. Sci. Rep. 2021 11 1 23587 10.1038/s41598‑021‑02864‑1 34880315
    [Google Scholar]
  30. Kitada M. Ogura Y. Suzuki T. Sen S. Lee S.M. Kanasaki K. Kume S. Koya D. A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity. Diabetologia 2016 59 6 1307 1317 10.1007/s00125‑016‑3925‑4 27020449
    [Google Scholar]
  31. Rolleman E.J. Krenning E.P. Bernard B.F. de Visser M. Bijster M. Visser T.J. Vermeij M. Lindemans J. de Jong M. Long-term toxicity of [177Lu-DOTA0,Tyr3]octreotate in rats. Eur. J. Nucl. Med. Mol. Imaging 2007 34 2 219 227 10.1007/s00259‑006‑0232‑1 17021812
    [Google Scholar]
  32. Sağol S. Özkinay E. Özşener S. Impaired antioxidant activity in women with pre‐eclampsia. Int. J. Gynaecol. Obstet. 1999 64 2 121 127 10.1016/S0020‑7292(98)00217‑3 10189019
    [Google Scholar]
  33. Kweider N. Huppertz B. Kadyrov M. Rath W. Pufe T. Wruck C.J. A possible protective role of Nrf2 in preeclampsia. Ann. Anat. 2014 196 5 268 277 10.1016/j.aanat.2014.04.002 24954650
    [Google Scholar]
  34. Tossetta G. Fantone S. Piani F. Crescimanno C. Ciavattini A. Giannubilo S.R. Marzioni D. Modulation of NRF2/KEAP1 signaling in preeclampsia. Cells 2023 12 11 1545 10.3390/cells12111545 37296665
    [Google Scholar]
  35. Burwick RM. Fichorova RN. Dawood HY. Yamamoto HS. Feinberg BB. Urinary excretion of C5b-9 in severe preeclampsia: tipping the balance of complement activation in pregnancy. Hypertension 2013 62 6 1040 1045 10.1161/HYPERTENSIONAHA.113.01420
    [Google Scholar]
  36. Isaksson G.L. Nielsen L.H. Palarasah Y. Jensen D.M. Andersen L.L.T. Madsen K. Bistrup C. Jørgensen J.S. Ovesen P.G. Jensen B.L. Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes. J. Hypertens. 2023 41 2 223 232 10.1097/HJH.0000000000003288 36583350
    [Google Scholar]
  37. Wong E.K.S. Kavanagh D. Diseases of complement dysregulation—an overview. Semin. Immunopathol. 2018 40 1 49 64 10.1007/s00281‑017‑0663‑8 29327071
    [Google Scholar]
  38. Girardi G. Complement activation, a threat to pregnancy. Semin Immunopathol. 2018 40 1 103 111 10.1007/s00281‑017‑0645‑x
    [Google Scholar]
  39. He Y. Xu B. Wang M. Wang Y. Yu F. Chen Q. Zhao M. Dysregulation of complement system during pregnancy in patients with preeclampsia: A prospective study. Mol. Immunol. 2020 122 69 79 10.1016/j.molimm.2020.03.021 32305690
    [Google Scholar]
  40. He Y. Xu B. Song D. Yu F. Chen Q. Zhao M. Correlations between complement system’s activation factors and anti-angiogenesis factors in plasma of patients with early/late-onset severe preeclampsia. Hypertens. Pregnancy 2016 35 4 499 509 10.1080/10641955.2016.1190845 27315511
    [Google Scholar]
  41. Qing X. Redecha P.B. Burmeister M.A. Tomlinson S. D’Agati V.D. Davisson R.L. Salmon J.E. Targeted inhibition of complement activation prevents features of preeclampsia in mice. Kidney Int. 2011 79 3 331 339 10.1038/ki.2010.393 20944547
    [Google Scholar]
  42. Nezu M. Souma T. Yu L. Sekine H. Takahashi N. Wei A.Z.S. Ito S. Fukamizu A. Zsengeller Z.K. Nakamura T. Hozawa A. Karumanchi S.A. Suzuki N. Yamamoto M. Nrf2 inactivation enhances placental angiogenesis in a preeclampsia mouse model and improves maternal and fetal outcomes. Sci. Signal. 2017 10 479 eaam5711 10.1126/scisignal.aam5711 28512147
    [Google Scholar]
  43. Kuang B. Wang Z. Hou S. Zhang J. Wang M. Zhang J. Sun K. Ni H. Gong N. Methyl eugenol protects the kidney from oxidative damage in mice by blocking the Nrf2 nuclear export signal through activation of the AMPK/GSK3β axis. Acta Pharmacol. Sin. 2023 44 2 367 380 10.1038/s41401‑022‑00942‑2 35794373
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240302343240801105324
Loading
/content/journals/cmm/10.2174/0115665240302343240801105324
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test