Cardiorenal interaction during the acute phase of experimental <i>Trypanosoma cruzi</i> infection: the influence of aldosterone and the AT1 receptor on mortality

Abstract

Introduction: Trypanosoma cruzi infection is a serious public health problem in Latin America. Despite positive results from programs directed to the interruption of vectorial transmission, there are still millions of people infected, and a large number, at the risk of infection. Chagas disease is typically associated with cardiac complications, and chronic symptoms include heart failure and megaesophagus development. Objective: In this study, we aimed to evaluate the importance of the cardiorenal axis and renin-angiotensin-aldosterone system (RAAS) activation in experimental T.cruzi infection. We also evaluated the influence of aldosterone and the angiotensin II receptor type 1 (AT1R) on the mortality of infected mice. Methods: BALB/c mice infected with the Y strain of T.cruzi were treated with spironolactone or losartan. We assessed parasitemia, mortality, and renal and cardiac function by using non-invasive methods. Results: Our data show that AT1R promotes an important (and necessary) inotropic positive effect in the heart and minimizes acute kidney injury. Conversely, aldosterone increases the release of K + and aggravates heart failure. It also has associated effects on the renal, cardiovascular, and cardiac electrical conduction systems. Consequently, the aldosterone antagonist reduced the mortality rate by 50%, whereas the AT1R antagonist increased it by 20%. Conclusions: The RAAS connects the cardiorenal systems, and its components differentially affect the mortality of animals experimentally infected by T.cruzi.

Could angiotensin-modulating drugs be relevant for the treatment of Trypanosoma cruzi infection? A systematic review of preclinical and clinical evidence

“…Most studies indicated that RAS-modulating drugs were effective in reducing parasitaemia (Chumbinho et al ., 2012; Leite et al ., 2017) and mortality (de Paula Costa et al ., 2010; Chumbinho et al ., 2012; Penitente et al ., 2015). Conversely, parasitaemia was unchanged by enalapril (Penitente et al ., 2015), while high doses of captopril (75 mg L −1 ) increased the animals’ mortality with no impact on heart parasitism (Leon et al ., 2003).…”

“…Only Chumbinho et al . (2012) analysed biochemical markers of organ toxicity (i.e. serum creatinine and urea), indicating that losartan increased kidney injury in T. cruzi -infected mice (Table 4).…”

“…In addition, the homogenous genetic background of isogenic animals improves the experimental control, providing a lower immunological variability than outbred animals (Trischmann et al ., 1978; Vorraro et al ., 2014). Furthermore, most studies used T. cruzi- resistant C57BL/6 mice (de Paula Costa et al ., 2010; Penitente et al ., 2015; Leite et al ., 2017), while only two cases reported susceptible BALB/c (Chumbinho et al ., 2012) or A/J (Leon et al ., 2003) mice. According to the differential parasitic susceptibility, the choice of these lineages (Silva et al ., 2013) should be essentially aligned with three central characteristics of infection, such as evolution time, parasite virulence/pathogenicity (Marinho et al ., 1999; Silva et al ., 2013) and inoculum size (Trischmann et al ., 1978).…”

Melatonin down-regulates steroidal hormones, thymocyte apoptosis and inflammatory cytokines in middle-aged T. cruzi infected rats

“…Chumbinho et al (2012) also described that the mortality rate in T. cruzi infected mice was under the direct influence of aldosterone. According to the same authors, aldosterone blockage with spironolactone (an aldosterone antagonist) attenuates the parasite load and reduces the severity of Chagas cardiomyopathy [ 49 ]. Currently is also known that a prolonged aldosterone treatment (between 4 and 5 weeks) triggers enhanced oxidative stress production and accounts for a proinflammatory phenotype.…”

Neglected Tropical Diseases with an Impact on Kidney Function

“…There is evidence of functional and structural kidney abnormalities after T. cruzi infection, associated with reduction in renal blood flow, proximal tubular damage, and inflammatory interstitial infiltrate. An observation is made of an increased production of pro-inflammatory cytokines and nitric oxide, as well as renal function loss associated with high parasitic load [9][10][11][12]. In the acute phase, the renal lesion is related to cardiovascular dysfunction, due to a transitory decrease in renal blood flow, which was demonstrated in experimental models [11,13].…”