Malaria infection promotes a selective expression of kinin receptors in murine liver

Abstract

Background Malaria represents a worldwide medical emergency affecting mainly poor areas. Plasmodium parasites during blood stages can release kinins to the extracellular space after internalization of host kininogen inside erythrocytes and these released peptides could represent an important mechanism in liver pathophysiology by activation of calcium signaling pathway in endothelial cells of vertebrate host. Receptors (B1 and B2) activated by kinins peptides are important elements for the control of haemodynamics in liver and its physiology. The aim of this study was to identify changes in the liver host responses (i.e. kinin receptors expression and localization) and the effect of ACE inhibition during malaria infection using a murine model. Methods Balb/C mice infected by Plasmodium chabaudi were treated with captopril, an angiotensin I-converting enzyme (ACE) inhibitor, used alone or in association with the anti-malarial chloroquine in order to study the effect of ACE inhibition on mice survival and the activation of liver responses involving B1R and B2R signaling pathways. The kinin receptors (B1R and B2R) expression and localization was analysed in liver by western blotting and immunolocalization in different conditions. Results It was verified that captopril treatment caused host death during the peak of malaria infection (parasitaemia about 45%). B1R expression was stimulated in endothelial cells of sinusoids and other blood vessels of mice liver infected by P. chabaudi . At the same time, it was also demonstrated that B1R knockout mice infected presented a significant reduction of survival. However, the infection did not alter the B2R levels and localization in liver blood vessels. Conclusions Thus, it was observed through in vivo studies that the vasodilation induced by plasma ACE inhibition increases mice mortality during P. chabaudi infection. Besides, it was also seen that the anti-malarial chloroquine causes changes in B1R expression in liver, even after days of parasite clearance. The differential expression of B1R and B2R in liver during malaria infection may have an important role in the disease pathophysiology and represents an issue for clinical treatments.

Polarized Proteins in Endothelium and Their Contribution to Function

“…This expression pattern aligns with well-described dominance of NO-based vasodilation in conduit arteries compared to resistance arteries [46]. While B 2 receptors are widely expressed throughout the healthy endothelium [50], B 1 expression is limited to the endothelium of cerebral [57] and hepatic [58] microvessels. Its expression in homeostasis is minimal; however, it is induced following peripheral tissue injury [59], in the presence of the proinflammatory cytokine interferon gamma [57], or following Plasmodium chabaudi infection [58].…”

Understanding the Pathophysiology of COVID-19: Could the Contact System Be the Key?

“…B1R-knockout mice presented a significant reduction of survival when compared with wild-type mice, unlike the B2R-knockout ones (72). In this inflammation/infection model, chloroquineinduced upregulation of B1R expression proved protective: the full meaning of this result is unclear but might indicate that the selective inhibition of B2R could represent a rational modulation of dysregulated BK pathway during infection.…”

“…Finally, it is interesting to observe that in an experimental malaria model ( Plasmodium parasites during blood stages release kinins), exposure to captopril (an ACE-inhibitor that leads to the reduction of BK degradation) resulted in death in mice, while the concomitant administration of chloroquine protected them. B1R-knockout mice presented a significant reduction of survival when compared with wild-type mice, unlike the B2R-knockout ones ( 72 ). In this inflammation/infection model, chloroquine-induced upregulation of B1R expression proved protective: the full meaning of this result is unclear but might indicate that the selective inhibition of B2R could represent a rational modulation of dysregulated BK pathway during infection.…”

Kinins and Their Receptors in Infectious Diseases

“…In an in vivo study, P. chabaudi infection was related to an upregulation of B 1 receptors in endothelial cells of sinusoids and other blood vessels of mouse liver. Of note, the anti-malarial drug chloroquine modulated the expression of B 1 receptors in this tissue [ 168 ]. A clinical study showed the activation of coagulation cascade in severe malaria caused by P. falciparum .…”