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

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 proinflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.

ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice

“…In our previous data, BSA challenge leads to inflammatory cytokine release and immune dysfunction in the cortical and medullary areas, which aggravates tubule damage and interstitial inflammation triggered by sepsis [11]. In addition, alterations in the albumin reabsorption machinery and changes in collagen deposition occur during this process [24]. We report here that ATRvD1 treatment reduced proteinuria excretion, UPC ratio, glomerular cell number and ECM deposition.…”

“…TGF activates pro-fibrotic pathways, leading to ECM deposition. BSA overload induces high TGF levels, which correlates with the renal damage [20,24]. Moreover, COL3 and COL4 are normally expressed in the kidney and are increased during fibrosis [31,32].…”

Oxidized Albumin as a Mediator of Kidney Disease

“…It has been determined that these changes are accompanied by tubular dilation, glomerular remodeling. and collagen deposition in addition to an increase in IL-6, TNF-α, and TGF-β [ 36 , 37 , 38 ]. On the other hand, randomized studies performed with critically ill patients have shown that the albumin overload (“hyper-oncotic albumin”) used to stabilize hemodynamics does not generate nephrotoxic effects during the hospital stay period [ 39 ].…”

High Doses of Essential Oil of Croton Zehntneri Induces Renal Tubular Damage

“…One of the main causes of the development of TII is albumin overload in the proximal tubule (PT) caused by increased filtration at the glomerular membrane [ 5 , 6 , 7 ]. This process induces functional changes in PT epithelial cells (PTECs), leading to the development of a pro-inflammatory and pro-fibrotic phenotype [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. In this context, identification of treatments for TII could represent a forward step to halt the progression of renal disease.…”

“…In the present study, we investigated the effect of EOCZ treatment in healthy Swiss mice and in a subclinical acute kidney injury (subAKI) animal model which developed TII induced by PT albumin overload [ 8 , 9 , 10 , 11 , 12 , 13 ]. Swiss mice were treated with 300 mg/kg/day EOCZ, a dose at the upper range of those used pharmacologically in previous studies [ 19 , 20 ].…”