Upregulation of miR-382 contributes to renal fibrosis secondary to aristolochic acid-induced kidney injury via PTEN signaling pathway

Abstract

Acute kidney injury (AKI) has a critical role in the development of chronic kidney disease (CKD). Building on our previous findings, we explored the role of miR-382 in facilitating the transition of AKI to CKD using the Aristolochic acid (AA) nephropathy model, which was induced by intraperitoneal injection of aristolochic acid I salt (10 or 20 mg/kg). The effects of genetic depletion, pharmacologic inhibition, or overexpression of miR-382 on the PTEN/AKT signaling pathway were examined in vivo and in vitro. Changes in renal pathology and renal epithelial polarity were evaluated. A luciferase reporter assay was performed to investigate the reciprocal suppression relationship between miR-382 and PTEN. Renal fibrosis developed 14 d after AA exposure in a dose-and time-dependent manner. Renal abundance of miR-382 was upregulated following AA treatment, while genetic depletion or pharmacological inhibition of miR-382 partially reversed renal tubulointerstitial fibrosis. Expression of PTEN, a target of miR-382, was downregulated and subsequently its downstream AKT signaling pathway was activated during AKI to CKD transition induced by AA. Inhibition of PTEN in vitro resulted in the acquisition of the EMT phenotypes. Furthermore, upregulation of miR-382 in renal epithelial cells was partially mediated by the activation of NF-kB signaling, with a substantial elevation of proinflammatory cytokines. An in vivo study revealed that either miR-382 knockdown or miR-382 knockout was pivotal for inflammatory suppression, while an in vitro experiment confirmed that upregulation of miR-382 in cultured MTEC cells under AA exposure was remarkably reversed by NF-kB siRNA. These data indicated a novel role for the NF-κB/miR-382/PTEN/AKT axis in the pathogenesis of tubulointerstitial fibrosis following AA-induced acute renal tubular epithelial injury. Targeting miR-382 may lead to a potential novel therapeutic approach for retarding the AKT to CKD transition.

WITHDRAWN: Dexamethasone reduces podocyte injury through the PTEN-PI3K/Akt signaling pathway

“…The distribution of PTEN in podocytes was abnormal, and there was a loss of PTEN distribution in the cell membrane and cytoplasm.After DEX treatment, the above changes could be reversed; furthermore, after PAN damaged podocytes, the expression of the PI3K p85, p-Ak, p-GSK3β and LC3B protein decreased, and the expression of the Bad protein increased. DEX treatment could reverse the changes described above; studies have also found that PTEN may be a kind of protective gene in the kidney [23][24][25][26][27] . High expression of PTEN can negatively regulate the PI3K/Akt pathway, inhibit the activation of Akt, improve the phenotype of renal podocytes, and reduce damage to renal podocytes [28] .In early DN, as glomerular damage increases, the expression of PTEN gradually decreases, suggesting that PTEN has a certain correlation with glomerular damage [29][30][31][32] .…”

“…Therefore, some scholars refer to this pathway as the PTEN-PI3K/AKT signal transduction pathway. In recent years, researchers have found that in addition to playing an important role in the eld of tumors, PTEN is also involved in the progression of kidney disease [9][10][11] . Studies have found that in animal models of diabetic nephropathy, the expression of PTEN in glomerular mesangial cells and podocytes is signi cantly downregulated, suggesting that PTEN may play an important role in glomerular sclerosis; in addition, as the expression of PTEN in the kidney is downregulated, podocytes are damaged, and urine protein levels gradually increase [12][13][14] ,suggesting that PTEN may be a protective gene in the kidney.…”

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury

“…MiR-143 also promotes fibrosis through targeting sprouty RTK signaling antagonist 3 (Spry3) to activate the p38-ERK-JNK signaling axis ( Li et al, 2019 ). MiR-382 promotes inflammation and fibrosis through targeting of PTEN and potentiation of the NFkB-AKT axis ( Wang et al, 2020 ). MiR-134 promotes inflammatory activation in macrophages through targeting angiopoietin-like 4 ( Lan et al, 2016 ).…”

Prospective Pharmacological Potential of Resveratrol in Delaying Kidney Aging

“…Additionally, NF-κB promotes inflammation and regulates apoptosis; these two factors are associated with the progression of CKD [ 188 ]. In an in vivo study with mice, the upregulation of microRNA-382 in kidney epithelial cells was mediated by the activation of NF-κB signaling, which elevates pro-inflammatory cytokines [ 189 ]. Ang II and NF-κB play a vital role in podocyte injury via membrane protein (Tmem) 63c [ 190 ].…”