The angiotensin II/AT1 receptor pathway mediates malaria-induced acute kidney injury.

ABSTRACT

Malaria-induced acute kidney injury (MAKI) is a life-threatening complication of severe malaria. Here, we investigated the potential role of the angiotensin II (Ang II)/AT1 receptor pathway in the development of MAKI. We used C57BL/6 mice infected by Plasmodium berghei ANKA (PbA-infected mice), a well-known murine model of severe malaria. The animals were treated with 20 mg/kg/day losartan, an antagonist of AT1 receptor, or captopril, an angiotensin-converting enzyme inhibitor. We observed an increase in the levels of plasma creatinine and blood urea nitrogen associated with a significant decrease in creatinine clearance, a marker of glomerular flow rate, and glomerular hypercellularity, indicating glomerular injury. PbA-infected mice also presented proteinuria and a high level of urinary γ-glutamyltransferase activity associated with an increase in collagen deposition and interstitial space, showing tubule-interstitial injury. PbA-infected mice were also found to have increased fractional excretion of sodium (FENa+) coupled with decreased cortical (Na++K+)ATPase activity. These injuries were associated with an increase in pro-inflammatory cytokines, such as tumor necrosis factor alpha, interleukin-6, interleukin-17, and interferon gamma, in the renal cortex of PbA-infected mice. All modifications of these structural, biochemical, and functional parameters observed in PbA-infected mice were avoided with simultaneous treatment with losartan or captopril. Our data allow us to postulate that the Ang II/AT1 receptor pathway mediates an increase in renal pro-inflammatory cytokines, which in turn leads to the glomerular and tubular injuries observed in MAKI.