Abstract:Podocyte apoptosis contributes to the pathogenesis of diabetic nephropathy (DN). However, the mechanisms that mediate high glucose (HG)-induced podocyte apoptosis remain poorly understood. Conditionally immortalized mouse podocytes were cultured in HG medium. A chemical inhibitor or a specific short-hairpin RNA (shRNA) vector was used to inhibit the activation of the Notch pathway and the PI3K/Akt pathway in HG-treated podocytes. Western blotting and real-time PCR were used to evaluate the levels of Notch, PI3… Show more
“…A previous study indicated that PI3K/Akt signaling pathway activation occurs in association with DN, and high sugar or transforming growth factor-β1 levels can cause changes to certain podocyte proteins such as ZO-1 and CD2AP by activating this pathway (27). Glomerular p-Akt expression in patients with DN has been observed to be increased with aggravation of the disease, although in severe lesions its expression is decreased and the expression of its negative regulation gene PTEN is gradually decreased with the increase of glomerular lesions; these results suggest that the PI3K/Akt signaling pathway is important in the development of early DN lesions (10,27). The present study found that emodin significantly promoted p-Akt protein expression in the rats with DN.…”
Abstract. Emodin is the main active component of the Chinese medicine rhubarb, which has a variety of pharmacological effects and a high clinical value. Its anti-inflammatory and antitumor effects have been widely studied. The aim of the present study was to determine whether emodin has renoprotective effects, and to identify the potential underlying mechanisms in a rat model of diabetic nephropathy (DN). The changes in mean blood glucose levels, normalized kidney weight, urinary albumin excretion, serum creatinine levels and tubulointerstitial injury index (TII) scores of the rats with DN were significantly attenuated by emodin. Furthermore, treatment with emodin significantly inhibited inflammation-related factors and oxidative stress, suppressed the expression of intercellular adhesion molecule 1 (ICAM-1) and B-cell lymphoma 2-associated X protein (Bax), increased phosphorylated Akt and phosphorylated-glycogen synthase kinase 3 (p-GSK-3β) expression and inhibited caspase-3 activity in diabetic rats. These data suggest that emodin protects against DN and that the underlying mechanism may involve the suppression of inflammation, ICAM-1 and Bax, and activation of the PI3K/Akt/GSK-3β pathway.
“…A previous study indicated that PI3K/Akt signaling pathway activation occurs in association with DN, and high sugar or transforming growth factor-β1 levels can cause changes to certain podocyte proteins such as ZO-1 and CD2AP by activating this pathway (27). Glomerular p-Akt expression in patients with DN has been observed to be increased with aggravation of the disease, although in severe lesions its expression is decreased and the expression of its negative regulation gene PTEN is gradually decreased with the increase of glomerular lesions; these results suggest that the PI3K/Akt signaling pathway is important in the development of early DN lesions (10,27). The present study found that emodin significantly promoted p-Akt protein expression in the rats with DN.…”
Abstract. Emodin is the main active component of the Chinese medicine rhubarb, which has a variety of pharmacological effects and a high clinical value. Its anti-inflammatory and antitumor effects have been widely studied. The aim of the present study was to determine whether emodin has renoprotective effects, and to identify the potential underlying mechanisms in a rat model of diabetic nephropathy (DN). The changes in mean blood glucose levels, normalized kidney weight, urinary albumin excretion, serum creatinine levels and tubulointerstitial injury index (TII) scores of the rats with DN were significantly attenuated by emodin. Furthermore, treatment with emodin significantly inhibited inflammation-related factors and oxidative stress, suppressed the expression of intercellular adhesion molecule 1 (ICAM-1) and B-cell lymphoma 2-associated X protein (Bax), increased phosphorylated Akt and phosphorylated-glycogen synthase kinase 3 (p-GSK-3β) expression and inhibited caspase-3 activity in diabetic rats. These data suggest that emodin protects against DN and that the underlying mechanism may involve the suppression of inflammation, ICAM-1 and Bax, and activation of the PI3K/Akt/GSK-3β pathway.
“…Indeed, a previous study from our group already demonstrated the participation of MAPK, ErbB, and Wnt signaling pathways during renal damage progression and their modulation after treatment with cytoprotective and anti-oxidant molecules (28). Moreover, different studies have established an interesting interplay between the Notch–PI3K/Akt and mTOR–PI3K/Akt pathways in the regulation of renal cells physiology (29–31). In line with this evidence, our results here demonstrated a strict association between differentially modulated miRNAs with regulatory pathways linked to positive modulation of transcription-dependent biological process, thereby highlighting the role of MSCs and MVs to restore normal renal function after AKI.…”
Mesenchymal stromal cells (MSCs) orchestrate tissue repair by releasing cell-derived microvesicles (MVs), which, presumably by small RNA species, modulate global gene expression. The knowledge of miRNA/mRNA signatures linked to a reparative status may elucidate some of the molecular events associated with MSC protection. Here, we used a model of cisplatin-induced kidney injury (acute kidney injury) to assess how MSCs or MVs could restore tissue function. MSCs and MVs presented similar protective effects, which were evidenced in vivo and in vitro by modulating apoptosis, inflammation, oxidative stress, and a set of prosurvival molecules. In addition, we observed that miRNAs (i.e., miR-880, miR-141, miR-377, and miR-21) were modulated, thereby showing active participation on regenerative process. Subsequently, we identified that MSC regulates a particular miRNA subset which mRNA targets are associated with Wnt/TGF-β, fibrosis, and epithelial–mesenchymal transition signaling pathways. Our results suggest that MSCs release MVs that transcriptionally reprogram injured cells, thereby modulating a specific miRNA–mRNA network.
“…For example, Notch signaling in hepatocytes is increased in response to high sugar concentrations [181] and hyperglycemia induced Jagged1 expression in endothelium was proposed to be an important mediator of diabetic vasculopathy [182]. Moreover, several investigators have shown that hyperglycemia elevates Notch receptor expression/signaling in cultured podocytes [183-185], and elevated Notch signaling has been linked to a loss of glomerular filtration due to a negative impact on podocyte function [186, 187]. Thus, hyperglycemic stimulation of Notch may be extremely important for understanding the pathology of diabetic nephropathy, especially since podocyte damage in diabetic kidneys has been proposed to be an early triggering event leading to other downstream renal complications [188].…”
The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.
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