Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia.

Simona Adesso,Tim Magnus,Björn Rissiek,Aldo Pinto,Salvatore Cuzzocrea,Giuseppina Autore,Michela Campolo,Stefania Marzocco,Orlando Paciello

doi:10.3389/fphar.2017.00370

Abstract

Indoxyl sulfate (IS) is a protein-bound uremic toxin resulting from the metabolism of dietary tryptophan which accumulates in patients with impaired renal function, such as chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15–60 μM) treatment in C6 astrocyte cells increased reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells. Inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, tumor necrosis factor-α and interleukin-6 release and nitrotyrosine formation were increased by IS (15–60 μM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications.

Highlights

Neurodegenerative diseases have become a growing health burden and, in our aging population, are often linked to other comorbidities
In order to assess the effect of indoxyl sulfate (IS) on oxidative stress in C6 cells, we evaluated intracellular reactive oxygen species (ROS) production
Oxidative stress and inflammation are essential for defense against injuries, but, if not properly regulated, they are capable of initiating various deleterious effects (Libetta et al, 2011)

Summary

Introduction

Neurodegenerative diseases have become a growing health burden and, in our aging population, are often linked to other comorbidities. Patients with CKD have many comorbidities such as immune disorders, with the coexistence of immunodeficiency and immune activation, and neurological complications that largely contribute to the morbidity and mortality of this disease (Buchman et al, 2009; Krishnan and Kiernan, 2009; Marzocco et al, 2010). CKD is frequently associated with cognitive impairment and, among patients with terminal CKD receiving haemodialysis, more than 85% have cognitive deficits (Krishnan and Kiernan, 2009). Causes of cognitive impairment in CKD are multifactorial and they include cerebrovascular disease, renal anemia, secondary hyperparathyroidism, dialysis disequilibrium, and uremic toxins accumulation. Plasmatic levels of uremic toxins increase as CKD progresses, and they are believed to be the main cause of cognitive impairment (Krishnan and Kiernan, 2009). IS is a nephro-vascular toxin (Niwa, 2010) that causes nephrotoxicity especially on tubular cells, inhibits proliferation

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