Administration of α-Galactosylceramide Improves Adenine-Induced Renal Injury.

Cristhiane Favero Aguiar,Érika L Naka,Angela Castoldi,Cristiane Naffah-De-Souza,Meire I Hiyane,Débora T R S Abate,Mariane T Amano,Niels O S Câmara,Marcos A Cenedeze,Matheus Corrêa-Costa,Alvaro Pacheco E Silva Filho,Tárcio T Braga

doi:10.2119/molmed.2014.00090

Abstract

Natural killer T (NKT) cells are a subset of lymphocytes that reacts to glycolipids presented by CD1d. Invariant NKT cells (iNKT) correspond to >90% of the total population of NKTs and reacts to α-galactosylceramide (αGalCer). αGalCer promotes a complex mixture of Th1 and Th2 cytokines, as interferon (IFN)-γ and interleukin (IL)-4. NKT cells and IFN-γ are known to participate in some models of renal diseases, but further studies are still necessary to elucidate their mechanisms. The aim of our study was to analyze the participation of iNKT cells in an experimental model of tubule-interstitial nephritis. We used 8-wk-old C57BL/6j, Jα18KO and IFN-γKO mice. They were fed a 0.25% adenine diet for 10 d. Both adenine-fed wild-type (WT) and Jα18KO mice exhibited renal dysfunction, but adenine-fed Jα18KO mice presented higher expression of kidney injury molecule-1 (KIM-1), tumor necrosis factor (TNF)-α and type I collagen. To analyze the role of activated iNKT cells in our model, we administered αGalCer in WT mice during adenine ingestion. After αGalCer injection, we observed a significant reduction in serum creatinine, proinflammatory cytokines and renal fibrosis. However, this improvement in renal function was not observed in IFN-γKO mice after αGalCer treatment and adenine feeding, illustrating that this cytokine plays a role in our model. Our findings may suggest that IFN-γ production is one of the factors contributing to improved renal function after αGalCer administration.

Highlights

Chronic kidney diseases (CKDs) are progressive scarring conditions characterized by a decrease in renal function over time affecting millions of people worldwide
To determine if the absence of Invariant NKT cells (iNKT) cells would play a role in adenine-induced tubule-interstitial nephritis (TIN), C57Bl/6J and Jα18KO mice were fed a 0.25% adenine diet for 10 d
We analyzed kidney mRNA expression of some molecules related to kidney injury as tumor necrosis factor (TNF)-α and kidney injury molecule-1 (KIM-1)

Summary

Introduction

Chronic kidney diseases (CKDs) are progressive scarring conditions characterized by a decrease in renal function over time affecting millions of people worldwide. A common final pathway of CKD is tubule-interstitial fibrosis, caused by excessive extracellular matrix deposition after chronic insults [1,2]. A physical or chemical injury (for example, hypertension, drugs and obstruction) may cause a release of inflammatory mediators, which recruit inflammatory cells to the site. Such an inflammatory process affects tubular cells and may lead to apoptosis, necrosis or activation of interstitial fibroblasts, which produce collagens leading to a fibrotic scar [3,4,5]. Adenine is produced endogenously but its longterm ingestion results in 2,8-dihydroxyadenine precipitation inside the renal tubules, leading to the formation of kidney stones, with extensive tubular dilation, inflammation, necrosis and fibrosis. The inflammatory process in this model is known to comprise the activation of toll-like receptors, inflammasome and nuclear factor (NF)-κB [2,7,8,9]

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