The mineralocorticoid receptor in chronic kidney disease.

Chronic kidney disease (CKD) is a major public health concern, affecting approximately 10% of the population worldwide. CKD of glomerular or tubular origin leads to the activation of stress mechanisms, including the renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) activation. Over the last two decades, blockade of the MR has arisen as a potential therapeutic approach against various forms of kidney disease. In this review, we summarize the experimental studies that have shown a protective effect of MR antagonists (MRAs) in nondiabetic and diabetic CKD animal models. Moreover, we review the main clinical trials that have shown the clinical application of MRAs to reduce albuminuria and, importantly, to slow CKD progression. Recent evidence from the FIDELIO trial showed that the MRA finerenone can reduce hard kidney outcomes when added to the standard of care in CKD associated with type 2 diabetes. Finally, we discuss the effects of MRAs relative to those of SGLT2 inhibitors, as well as the potential benefit of combination therapy to maximize organ protection. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc.

Plasma Proteins and Platelets Modulate Neutrophil Clearance of Malaria-Related Hemozoin Crystals.

Hemozoin is an insoluble crystalline pigment produced by the malaria parasite Plasmodia upon digesting host hemoglobin inside red blood cells. Red blood cell rupture releases hemozoin crystals into the circulation from where they are cleared by phagocytes such as neutrophils. We speculated that plasma proteins would affect the ability of neutrophils to clear hemozoin crystals. To test this, we cultured human blood neutrophils with hemozoin ex vivo and found that neutrophils ingested hemozoin (0.1-1 µm crystal size) in a dose-dependent manner into phagosomes and vesicles/vacuoles, resulting in morphological changes including nuclear enlargement, and vesicle formation, but not cell membrane rupture or release of neutrophil extracellular traps. The presence of human plasma significantly inhibited the ability of neutrophils to ingest hemozoin crystals. Platelet-poor plasma further inhibited the uptake of hemozoin by neutrophils. Selective exposure to fibrinogen completely replicated the plasma effect. Taken together, neutrophils cleared hemozoin crystals from the extracellular space via endocytosis into phagosomes and vesicles without inducing the release of neutrophil extracellular traps. However, human plasma components such as fibrinogen limited hemozoin clearance, whereas the presence of platelets augmented this process. These factors may influence the pro-inflammatory potential of hemozoin crystals in malaria.