Ulinastatin ameliorates preeclampsia induced by N(gamma)-nitro-l-arginine methyl ester in a rat model via inhibition of the systemic and placental inflammatory response

J Hypertens. 2023 Jan 1;41(1):150-158. doi: 10.1097/HJH.0000000000003316. Epub 2022 Nov 9.

Abstract

Background: The pathogenesis of preeclampsia (PE) is associated with inflammation and endothelial damage. Ulinastatin (UTI) mainly inhibits proteolytic activity and significantly reduces the release of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) from macrophages. It also ameliorates vascular endothelial damage in pathological conditions. Hence, we investigated the effects of UTI in a rat model of PE induced using N(gamma)-nitro-l-arginine methyl ester (L-NAME).

Methods: Although inducing PE in a rat model, 5000 U/kg of UTI were injected daily. Systolic blood pressure (SBP) and protein levels in the urine were measured. Renal function, and serum concentrations of TNF-α, IL-6, placental growth factor (PLGF), and von Willebrand factor (vWF) were evaluated. The number and weight of live fetuses as well as the weight of placentas were measured. Placentas were collected for western blot and pathological analysis.

Results: UTI slightly ameliorated proteinuria and the increases in SBP, blood urea nitrogen (BUN), and serum creatinine. Furthermore, UTI improved serum and placental protein expression levels of TNF-α, IL-6, vWF, and PLGF. Pathological analysis revealed that vascular density and blood flow perfusion was enhanced, vessel wall thickening and neutrophil infiltration were diminished, and the weight and number of live fetuses as well as the weight of the placentas were improved with UTI.

Conclusion: Preventive use of UTI in the PE rat model induced by L-NAME partially alleviated hypertension, proteinuria, and impaired renal function; improved fetal growth restriction; diminished vascular endothelial injury; and ameliorated placental vasculogenesis abnormality and malperfusion by inhibiting the systemic and placental inflammatory response, suggesting that UTI is a potential drug for PE prevention or treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Humans
  • Interleukin-6
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Placenta
  • Placenta Growth Factor
  • Pre-Eclampsia* / drug therapy
  • Pregnancy
  • Proteinuria / drug therapy
  • Rats
  • Tumor Necrosis Factor-alpha
  • von Willebrand Factor

Substances

  • Placenta Growth Factor
  • urinastatin
  • arginine methyl ester
  • von Willebrand Factor
  • Tumor Necrosis Factor-alpha
  • Interleukin-6
  • NG-Nitroarginine Methyl Ester