Effects of Tristetraprolin on Doxorubicin (Adriamycin)-induced experimental nephrotic syndrome though inhibiting IL-13 /STAT6 signal pathway

Abstract

Background: To study the effects of Tristetraprolin (TTP) on Doxorubicin (DOX)-induced experimental kidney injury (KI). Methods: DOX was used to induce kidney injury in Balb/c male mice (in vivo) and in human kidney proximal tubular epithelial cell line (HK-2) and normal rat kidney epithelial cell line (NRK-52E) (in vitro). Body weight of the animal groups under investigation were recorded daily throughout the experimental period. Histological changes were observed using Hematoxylin-eosin (HE) staining, and levels of blood urea nitrogen, serum creatinine and serum cystatin C in KI mice, and ROS, MDA, LDH and SOD in cells were detected using the corresponding kits. Meanwhile, intracellular levels of oxidative stress were assessed using 2, 7-dichlorodihydrofluorescein diacetate (DCF-DA) fluorescent staining. TTP and Kim-1 expression levels were measured by immunohistochemistry and western blot. The TNF-α, IL-1β and IL-6 levels were evaluated by ELISA. Expressions of IL-13, STAT6, p-STAT6, Bcl-2, Bax, cleaved-caspase3 were detected via western blot, respectively. CCK-8 was conducted for analyzing cell viability, and cells apoptosis were assessed by DAPI staining and flow cytometry. Results: DOX treatment decreased body weight and aggravated renal injury without changes in water and food intake. DOX significantly reduced TTP expression, stimulated IL-13/STAT6 pathway and elevated the levels of several factors related to renal injury, including inflammatory response, oxidative stress and cell apoptosis, which were significantly restored by the treatment of overexpression TTP in vitro. Conclusion: Overexpression of TTP significantly reduces DOX-induced adverse outcomes so as to prevent renal injury. Inhibition of IL-13/STAT6 pathway may be the functional mechanism under TTP in experimental KI.

Increased ketohexokinase-A governs fructose-induced podocyte hypertrophy by IL-6/STAT3 signaling activation

“…TTP has been reported to be a negative regulator of inflammatory cytokine IL-6 Zhang et al, 2020). Its low expression was detected in glomeruli of fructose-fed rats and fructose-exposed HPCs, which were consistent with that in glomeruli of diabetic kidney disease patients (Guo et al, 2020).…”

“…Its low expression was detected in glomeruli of fructose-fed rats and fructose-exposed HPCs, which were consistent with that in glomeruli of diabetic kidney disease patients (Guo et al, 2020). TTP overexpression obviously decreases IL-6 levels in human proximal tubular epithelial cells (Zhang et al, 2020). Its knockdown enhances podocyte injury marker claudin-1 expression and inflammatory response (Guo et al, 2020).…”

“…Tristetraprolin (TTP), known as an anti-inflammatory factor, can mediate the degradation of mRNAs of inflammatory factors (Guo et al, 2020). TTP expression is obviously decreased, accompanied with elevated IL-6 level in mouse kidney of doxorubicin-induced nephrotic syndrome (Zhang et al, 2020). Its down-regulation is negatively correlated with IL-6 expression in diabetic patients with proteinuria (Liu et al, 2015).…”

Anti-oxidant impact of Lisinopril and Enalapril against acute kidney injury induced by doxorubicin in male Wistar rats: involvement of kidney injury molecule-1

“…The free radical production may be attributed to DOX's chemical constituent of the water-insoluble planar tetracycline which binds to the water-soluble sugar daunosamin. Furthermore, DOX itself can be transformed into a free radical that reacts with oxygen resulting in oxidative stress and ultimately cell death following the release of superoxide [ 4 ]. DOX has also been recorded to exert apoptotic effects by affecting mainly the mitochondrial pathway [ 5 ].…”

Transcriptomic analysis of the mechanisms of alleviating renal interstitial fibrosis using the traditional Chinese medicine Kangxianling in a rat model

“…This pathway was shown to delay the pathogenesis of glomerular sclerosis, providing a protective effect on the kidneys 14 . Kangxianling (KXL, anti-fibrin) is a traditional Chinese herbal formula that can significantly reduce the levels of serum creatine, total cholesterol, and ECM deposition and inhibit renal fibrosis 15 . In previous clinical studies, KXL significantly decreased serum creatinine (Scr) and blood urea nitrogen (BUN) levels as well as delayed the progression of chronic renal failure.…”