Indoxyl sulfate impairs erythropoiesis at BFU-E stage in chronic kidney disease.

Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of kidney function. It is associated with high serum levels of uremic toxins (UT), such as Indoxyl Sulfate (IS), which may participate in the genesis of several uremic complications. Anemia is one of the major complications in CKD patients that contribute to cardiovascular disease, increase morbi-mortality, and is associated with a deterioration of kidney failure in these patients. Our study aimed to characterize the impact of IS on CKD-related erythropoiesis. Using cellular and pre-clinical models, we studied cellular and molecular effects of IS on the growth and differentiation of erythroid cells. First, we examined the effect of clinically relevant concentrations of IS (up to 250 µM) in the UT7/EPO cell line. IS at 250 µM increased apoptosis of UT7/EPO cells at 48 h compared to the control condition. We confirmed this apoptotic effect of IS in erythropoiesis in human primary CD34+ cells during the later stages of erythropoiesis. Then, in IS-treated human primary CD34+ cells and in a (5/6 Nx) mice model, a blockage at the burst-forming unit-erythroid (BFU-E) stage of erythropoiesis was also observed. Finally, IS deregulates a number of erythropoietic related genes such as GATA-1, Erythropoietin-Receptor (EPO-R), and ß-globin. Our findings suggest that IS could affect cell viability and differentiation of erythroid progenitors by altering erythropoiesis and contributing to the development of anemia in CKD.

Non-Coding RNAs in Kidney Diseases: The Long and Short of Them.

Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene regulation. Moreover, understanding their biological roles in the physiopathology of many diseases, including renal, is a new challenge. lncRNAs regulate the effects of microRNAs (miRNA) on mRNA expression. Understanding the complex crosstalk between lncRNA-miRNA-mRNA is one of the main challenges of modern molecular biology. This review aims to summarize the role of lncRNA on kidney diseases, the molecular mechanisms involved, and their function as emerging prognostic biomarkers for both acute and chronic kidney diseases. Finally, we will also outline new therapeutic opportunities to diminish renal injury by targeting lncRNA with antisense oligonucleotides.

Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review.

Chronic kidney disease (CKD) is a global health problem characterized by progressive kidney failure due to uremic toxicity and the complications that arise from it. Anemia consecutive to CKD is one of its most common complications affecting nearly all patients with end-stage renal disease. Anemia is a potential cause of cardiovascular disease, faster deterioration of renal failure and mortality. Erythropoietin (produced by the kidney) and iron (provided from recycled senescent red cells) deficiencies are the main reasons that contribute to CKD-associated anemia. Indeed, accumulation of uremic toxins in blood impairs erythropoietin synthesis, compromising the growth and differentiation of red blood cells in the bone marrow, leading to a subsequent impairment of erythropoiesis. In this review, we mainly focus on the most representative uremic toxins and their effects on the molecular mechanisms underlying anemia of CKD that have been studied so far. Understanding molecular mechanisms leading to anemia due to uremic toxins could lead to the development of new treatments that will specifically target the pathophysiologic processes of anemia consecutive to CKD, such as the newly marketed erythropoiesis-stimulating agents.