IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload.

Diogo B Peruchetti,Maria Das Graças Henriques,Celso Caruso-Neves,João Luiz Silva-Filho,Douglas E Teixeira,Christina M Takiya,Mariana C Souza,Rodrigo P Silva-Aguiar,Ana Acacia S Pinheiro

doi:10.3389/fphys.2020.00172

Abstract

Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα–/– mice treated with saline; and (4) KO + BSA, IL4Rα–/– mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4+ T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the pro-inflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.

Highlights

There is a strict correlation between acute kidney injury (AKI) and chronic kidney disease (CKD), a public health problem with a high level of morbidity and mortality (Liyanage et al, 2015; Negi et al, 2018)
The decrease in albumin endocytosis and megalin expression were more pronounced in the KO + bovine serum albumin (BSA) than in BSA group. Together these results indicate that IL-4/IL-4 receptor α (IL-4Rα) pathway attenuate changes in proximal tubule (PT) albumin endocytosis machinery in tubule-interstitial injury (TII) induced by PT albumin overload
We used a subclinical AKI animal model to study the role of IL-4 on TII induced by albumin overload

Summary

Introduction

There is a strict correlation between AKI and CKD, a public health problem with a high level of morbidity and mortality (Liyanage et al, 2015; Negi et al, 2018). Several studies have demonstrated an important role of albumin overload in the PT in the development of TII (Gorriz and Martinez-Castelao, 2012; Erkan, 2013; Portella et al, 2013; Abreu et al, 2014; Landgraf et al, 2014; Teixeira et al, 2019) This mechanism requires changes in the albumin endocytosis machinery (Nakhoul and Batuman, 2011; Gorriz and MartinezCastelao, 2012; Landgraf et al, 2014; Teixeira et al, 2019). Some studies have shown that megalin works as sensor and integrator between changes in albumin concentration and PTEC injury (Caruso-Neves et al, 2006; Erkan, 2013; Peruchetti et al, 2014; Nielsen et al, 2016). Changes in megalin expression have been correlated with TII in Fanconi syndrome as well as autoimmune renal diseases (Piwon et al, 2000; Christensen et al, 2003; Batuman, 2007; Nakhoul and Batuman, 2011; Vicinanza et al, 2011; Gaide Chevronnay et al, 2014; Eshbach and Weisz, 2017; Wang et al, 2017; Cez et al, 2018)

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