Involvement of Inflammatory Cytokines, Renal NaPi-IIa Cotransporter, and TRAIL Induced-Apoptosis in Experimental Malaria-Associated Acute Kidney Injury

Author:

Simião Gustavo Martins1,Parreira Kleber Simônio2,Klein Sandra Gabriela3,Ferreira Flávia Batista34,Freitas Fernanda de Souza2,Silva Eduardo Ferreira da2,Silva Neide Maria4ORCID,Silva Murilo Vieira da3ORCID,Lima Wânia Rezende123

Affiliation:

1. Faculty of Health Sciences, Federal University of Rondonopolis, Rondonópolis 78736-900, MT, Brazil

2. Institute of Biotechnology, Federal University of Catalao, Catalão 75706-881, GO, Brazil

3. Laboratory of Biotechnology in Experimental Models, Federal University of Uberlandia, Uberlândia 38410-337, MG, Brazil

4. Institute of Biomedical Sciences, Federal University of Uberlandia, Uberlândia 38405-318, MG, Brazil

Abstract

The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA was used to investigate the relationship among pro-inflammatory cytokines, alterations in renal function biomarkers, and the induction of the TRAIL apoptosis pathway during malaria-associated acute kidney injury (AKI). Renal function was evaluated through the measurement of plasma creatinine and blood urea nitrogen (BUN). The mRNA expression of several cytokines and NaPi-IIa was quantified. Kidney sections were examined and cytokine levels were assessed using cytometric bead array (CBA) assays. The presence of glomerular IgG deposits and apoptosis-related proteins were investigated using in situ immunofluorescence assays and quantitative real-time PCR, respectively. NaPi-IIa downregulation in the kidneys provided novel insights into the pathogenesis of hypophosphatemia during CM. Histopathological analysis revealed characteristic features of severe malaria-associated nephritis, including glomerular collapse and tubular alterations. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, were upregulated. The TRAIL apoptosis pathway was significantly activated, implicating its role in renal apoptosis. The observed alterations in renal biomarkers and the downregulation of NaPi-IIa shed light on potential mechanisms contributing to renal dysfunction in ECM. The intricate balance between pro- and anti-inflammatory cytokines, along with the activation of the TRAIL apoptosis pathway, highlights the complexity of malaria-associated AKI and provides new therapeutic targets.

Funder

Fundação de Assistência à Pesquisa do Estado de Mato Grosso

Fundação de Assistência à Pesquisa do Estado de Minas Gerais

Rede Mineira de Biotecnologias em Modelos Experimentais

Publisher

MDPI AG

Reference66 articles.

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