23: Chronic nitric oxide inhibition in a rat model of preeclampsia (PE) leads to urinary proteomic biomarker signatures similar to humans

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• Objective
• Study design
• Results
• Conclusion
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Objective 

Urine proteomic profiling identified specific non-random N-terminus cleavage fragments of albumin as biomarkers characteristic of severe PE. Chronic NO inhibition in rats produces a PE-like syndrome (hypertension, proteinuria). We investigated whether NO blockade induces changes in the rat urine proteomic profile comparable to that observed in women with PE.

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Study design 

Osmotic pumps delivering saline (CRL; n=10) or L-NAME 50 mg/rat/day (LN; n=14) were inserted on d17 of gestation (term=d22). Animals were sacrificed on d21. Urine was obtained by trans-vesical aspiration. SELDI mass spectrometry and de-novo sequencing in MS/MS mode was used for proteomic profiling and biomarker identification. Validation experiments included urine and serum ELISA for albumin and sFlt-1. Urine SELDI tracings from women with severe PE (n=10) and normotensive controls (n=10) were used for comparison. Bioinformatics was used to identify similarity/dissimilarity between human and rat.

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Results 

LN rats had IUGR pups (p<0.001), higher urinary albumin (p<0.001) and plasma sFlt-1 (p=0.01) levels compared with CRL. Plasma sFlt-1 levels correlated with urinary albumin levels (r=0.5, p<0.01). 5 biomarkers were exclusively present in LN rats (P1-P5, Figure). MS/MS identified the rat biomarkers as fragments of albumin. In silico analysis located cleavage sites in identical positions to those seen in humans: P1 corresponded to the first N-terminal 24 aa of rat (2790 Da) and human albumin (2754 Da).

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Conclusion 

In the rat PE-like syndrome, the urine proteomic signature generated by specific fragments of albumin is similar to that seen in humans, thereby emphasizing the relevance of this model for the pathogenesis of human PE.