RETRACTED ARTICLE: Inhibition of inflammation using diacerein markedly improved renal function in endotoxemic acute kidney injured mice

Abstract

BackgroundInflammation is an important pathogenic component of endotoxemia-induced acute kidney injury (AKI), finally resulting in renal failure. Diacerein is an interleukin-1β (IL-1β) inhibitor used for osteoarthritis treatment by exerting anti-inflammatory effects. This study aims to investigate the effects of diacerein on endotoxemia-induced AKI.MethodsMale C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS, 10 mg/kg) for 24 h prior to diacerein treatment (15 mg/kg/day) for another 48 h. Mice were examined by histological, molecular and biochemical approaches.ResultsLPS administration showed a time-dependent increase of IL-1β expression and secretion in kidney tissues. Diacerein treatment normalized urine volume and osmolarity, reduced blood urea nitrogen (BUN), fractional excretion of sodium (FENa), serum creatinine and osmolarity, and protected renal function in an endotoxemic AKI mice model. In the histopathologic study, diacerein also improved renal tubular damage such as necrosis of the tubular segment. Moreover, diacerein inhibited LPS-induced increase of inflammatory cytokines, such as IL-1β, tumor necrosis factor-α, monocyte chemoattractant protein-1 and nitric oxide synthase 2. In addition, LPS administration markedly decreased aquaporin 1 (AQP1), AQP2, AQP3, Na,K-ATPase α1, apical type 3 Na/H exchanger and Na-K-2Cl cotransporter expression in the kidney, which was reversed by diacerein treatment. We also found that diacerein or IL-1β inhibition prevented the secretion of inflammatory cytokines and the decrease of AQP and sodium transporter expression induced by LPS in HK-2 cells.ConclusionOur study demonstrates for the first time that diacerein improves renal function efficiently in endotoxemic AKI mice by suppressing inflammation and altering tubular water and sodium handing. These results suggest that diacerein may be a novel therapeutic agent for the treatment of endotoxemic AKI.

Time-Dependent miRNA Profile during Septic Acute Kidney Injury in Mice

“…Mass spectrometry analysis of the same renal samples revealed that the concentration of apuaporin-1 (Aqp1), an already validated target of miR-144-3p [28] decreased at 24 h when miR-144-3p was upregulated, suggesting a possible regulation of Aqp1 by miR-144-3p. LPS downregulated both mRNA and protein expression of Aqp1 in mouse kidneys [29,30]. Just as in our study, Aqp1 protein was first elevated and later decreased in the kidney [30].…”

Sepsis associated acute kidney injury

“…A large body of preclinical work has investigated several pathways to potentially intervene and prevent or treat SA-AKI, and although this work has focused on molecules such as the caspase and interleukin inhibitors, to date it has not translated into human investigations of SA-AKI 162163164165Table 5. summarizes several clinical trials that have investigated novel and traditional agents in the setting of SA-AKI.…”

The Inflammatory Process Modulates the Expression and Localization of WT1 in Podocytes Leading to Kidney Damage

“…WT1 plays an important role in the genitourinary development and maintenance of podocytes throughout life (9). WT1 mutations are associated with a broad spectrum of clinical phenotypes (11,26,27), immunosuppressive treatment and renal alterations indicate that immunity and inflammation play an important role in the pathogenesis of diabetic kidney disease (28) and nephrotic syndrome (29). The steroid-resistant nephrotic syndrome is due to the loss of WT1 function during the development and maintenance of podocytes (7,11) and corticosteroids are the mainstay of treatment (29) and have reduced the death rate to around 3% (30).…”

“…There is increasing evidence that immunity and low-grade inflammation are an important component of the pathogenesis of diabetic kidney disease. Inflammation has become a center of interest in kidney injury, along with increased levels of inflammatory cytokines, such as IL1β, TNFα and monocyte chemoattractant protein-1 both in patients and in experimental models (28). The objective of this study was to analyze how the inflammatory process modulates the expression and posttranslational activity of WT1 and how it affects its functionality as a transcription factor in podocytes in mice treated with LPS.…”