Renal proximal tubule cells have a remarkable ability to reabsorb large quantities of albumin through megalin-mediated endocytosis. This is an essential process for overall body homeostasis. Overstressing this endocytic system with a prolonged excess of albumin is injurious to proximal tubule cells. How these cells function and protect themselves from injury is unknown. Here, we show that megalin is the sensor that determines whether cells will be protected or injured by albumin. Megalin, through a novel mechanism, binds PKB in a D-3-phosphorylated phospholipidinsensitive manner, anchoring PKB in the luminal plasma membrane. Whereas low doses of albumin are protective, an overload of albumin decreases megalin expression followed by a reduction of plasma membrane PKB, PKB activity, and Bad phosphorylation induced by PKB. The result is albumin-induced apoptosis. These results reveal a model for PKB distribution in the plasma membrane and elucidate mechanisms involved in both the protective and toxic effects of albumin on proximal tubule cells. In addition, our findings suggest a mechanism for the progression of chronic kidney disease to end-stage renal disease.albumin endocytosis ͉ apoptosis ͉ renal disease ͉ signal transduction ͉ tubular transport

Malaria in Pregnancy (MiP) is characterized by placental accumulation of Plasmodium -infected erythrocytes, intrauterine growth restriction (IUGR) and preterm delivery (PTD). Placental ATP-binding cassette (ABC) transporters mediate the efflux of nutrients, cytokines and xenobiotics. The expression and activity of these transporters are highly responsive to infection. We hypothesized that MiP would perturb the expression of placental ABC transporters, promoting PTD. Peripheral blood, spleens, livers and placentas of pregnant mice, infected with Plasmodium berghei ANKA on gestational day (GD) 13.5, were collected and analyzed on GD18.5. The primary consequences of human MiP, including IUGR, PTD (20%) and placental inflammation, were recapitulated in our mouse model. Electron microscopy revealed attenuated presence of labyrinthine microvilli and dilated spongiotrophoblasts -granular endoplasmic reticulum cisternae. Additionally, a decrease in placental Abca1 ( ABCA1), Abcb1b ( P-glycoprotein), Abcb9 and Abcg2 ( BCRP) expression was observed in MiP mice. In conclusion, MiP associated with PTD impairs placental ABC transporters’ expression, potentially modulating placental nutrient, environmental toxin and xenobiotic biodistribution within the fetal compartment, and may, at some degree, be involved with pregnancy outcome in MiP.

The contribution of T cells in severe malaria pathogenesis has been described. Here, we provide evidence for the potential role of angiotensin II (Ang II) in modulating splenic T cell responses in a rodent model of cerebral malaria. T cell activation induced by infection, determined by 3 to 4-fold enhancement in CD69 expression, was reduced to control levels when mice were treated with 20 mg/kg losartan (IC50 = 0.966 mg/kg/d), an AT1 receptor antagonist, or captopril (IC50 = 1.940 mg/kg/d), an inhibitor of angiotensin-converting enzyme (ACE). Moreover, the production of interferon-γ and interleukin-17 by CD4+ T cells diminished 67% and 70%, respectively, by both treatments. Losartan reduced perforin expression in CD8+ T cells by 33% while captopril completely blocked it. The upregulation in chemokine receptor expression (CCR2 and CCR5) observed during infection was abolished and CD11a expression was partially reduced when mice were treated with drugs. T cells activated by Plasmodium berghei ANKA antigens showed 6-fold enhance in AT1 levels in comparison with naive cells. The upregulation of AT1 expression was reduced by losartan (80%) but not by captopril. Our results suggest that the AT1/Ang II axis has a role in the establishment of an efficient T cell response in the spleen and therefore could participate in a misbalanced parasite-induced T cell immune response during P. berghei ANKA infection.

These results suggest that sepsis induces long-term effects in kidney structure aggravating tubule damage in a second kidney insult.