What are some examples of misfolded urinary proteins associated with preeclampsia?

Misfolded Urinary Proteins in Preeclampsia

SERPINA1 (α1-antitrypsin) peptide fragments and albumin fragments are the primary misfolded urinary proteins associated with preeclampsia, with SERPINA1 being particularly associated with severe forms requiring early delivery. 1

Key Misfolded Proteins in Preeclampsia

Primary Misfolded Proteins

• SERPINA1 (α1-antitrypsin) fragments:

  • The 21 amino acid C-terminus fragment is highly associated with severe preeclampsia requiring early delivery 1
  • Shows increased and aberrant immunoreactivity in urine, serum, and placenta of preeclamptic women 1
  • Seven specific SERPINA1 peptides demonstrate 52% sensitivity and 100% specificity for preeclampsia 2
  • Associated with the most severe forms of preeclampsia, particularly in terms of systolic hypertension and proteinuria 2

• Albumin fragments:

  • Nonrandom cleavage products of albumin appear in the urine of preeclamptic women 1
  • These fragments form part of the characteristic proteomic fingerprint of preeclampsia 1

Characteristics of Misfolded Proteins

• Misfolded proteins in preeclampsia demonstrate congophilia (binding to Congo red dye) 3, 4
• This property allows for detection using Congo red-based assays 4
• Protein carbonylation is elevated in preeclampsia and weakly correlates with protein misfolding (r=0.3) 5

Clinical Significance

Diagnostic Value

• The proteomic fingerprint of SERPINA1 and albumin fragments can:

  • Accurately diagnose preeclampsia 1
  • Distinguish preeclampsia from other hypertensive or proteinuric disorders in pregnancy 1
  • Predict preeclampsia requiring mandated delivery with high accuracy 1

• Congo red-based detection of misfolded proteins shows:

  • 74% detection rate with 3.0% false positive rate 4
  • 83% detection rate in severe preeclampsia cases 4
  • 86% detection rate in preterm preeclampsia cases 4

Predictive Value

• Abnormal urinary protein profiles can be detected more than 10 weeks before clinical manifestation of preeclampsia 1
• Current research is evaluating misfolded proteins as biomarkers for imminent prediction of preeclampsia in women with suspected cases 3

Pathophysiological Implications

Placental Involvement

• Increased SERPINA1 expression in placental villi and vascular spaces is observed in preeclampsia 1
• Significant perivascular deposits of misfolded SERPINA1 aggregates are exclusively identified in preeclamptic placentae 1
• SERPINA1 peptides are associated with syncytiotrophoblast membrane destruction and degradation 2
• Increased synthesis of SERPINA1 in the trophoblast leads to protein accumulation in fibrinoid deposits 2

Potential Mechanism

• SERPINA1 misfolding appears to be a novel pathophysiological mechanism in preeclampsia 1
• Increased expression of SERPINA1 in placental structural elements may reflect a protective mechanism against hypoxia 2
• Protein accumulation may block syncytial knots and placenta villi, decreasing trophoblast invasion 2

Clinical Applications

Current Status

• Current guidelines do not yet recommend testing for misfolded proteins in routine clinical practice 6
• Research is ongoing to establish accurate prediction models by combining misfolded protein detection with other clinical indicators 3

Future Potential

• Point-of-care urinary tests for misfolded proteins show promise for preeclampsia screening in late pregnancy 4
• Understanding of SERPINA1 misfolding may offer new therapeutic opportunities in the future 1
• Estimation of SERPINA1 peptides in urine could potentially be used to assess preeclampsia severity and determine treatment needs, including the necessity for urgent delivery 2

The identification of these misfolded urinary proteins not only provides diagnostic and predictive biomarkers but also offers insights into the pathophysiology of preeclampsia that may lead to novel therapeutic approaches in the future.