Regulatory effect of cortisol in immune response and it relationship with early biomarkers in renal disease in canine leishmaniasis

Abstract

Domestic dogs are the main urban reservoirs of Leishmania infantum, the causative agent of Visceral Leishmaniasis (VL) in the Americas. In VL endemic regions, the number of cases in humans is associated with the rate of canine infection. In CanL, sick dogs mount an inefficient cellular immune response (Th1) to fight the parasite concomitantly with an increase in the humoral immune response (Th2). In visceral leishmaniasis, the inflammatory cytokines produced can modulate the HPA axis (Hypothalamus, Pituitary Adrenal) causing increased production of corticotropin-releasing hormone (CRH) by the hypothalamus and induce the pituitary to synthesize adrenocorticotropic hormone (ACTH) and the adrenal glands to produce steroids, glucocorticoids, dehydroepiandrosterone that can modulate the immune response. In an experimental model, high levels of cortisol were positively correlated with interleukin IL-6, IL-1², IL-10 and TGF-² and arginase 1, while IFN-³ and iNOS showed a negative correlation, suggesting that cortisol may be involved in the pathogenesis of the disease, but in dogs with leishmaniasis the regulatory effect on cortisol on immunity has not yet been clarified. Additionally, high levels of cortisol in dogs can affect kidney function; and in human patients with visceral leishmaniasis, increased cortisol was associated with decreased glomerular filtration rate, indicating a relationship between cortisol and renal function. In canine leishmaniasis, although dermal manifestations and lymphadenopathy are the most common manifestations, renal disease is considered the main cause of mortality. Most dogs with leishmaniasis have kidney disease, but its detection in the terminal phase makes treatment difficult, so finding early markers in the urine that show kidney damage is essential to guide clinical management. Podocin, nephrin and miRNAs have been characterized as early markers of kidney damage in humans, however the evaluation of these markers in the urine of dogs with visceral leishmaniasis has not been studied. In the progression of the canine disease, there is immunosuppression and renal failure, which may be associated with increased cortisol, which has not yet been investigated in canine leishmaniasis. Knowledge of factors associated with disease progression can provide relevant information for the development of new treatment strategies for canine leishmaniasis. (AU)