Ski‐related novel protein suppresses the development of diabetic nephropathy by modulating transforming growth factor‐β signaling and microRNA‐21 expression

Abstract

Unveiling the mechanisms that drive the pathological phenotypes of diabetic nephropathy (DN) could help develop new effective therapeutics for this ailment. Transforming growth factor‐β1 (TGF‐β1)/Smad3 signaling is aberrantly induced in DN, leading to elevated microRNA‐21 (miR‐21) expression and tissue fibrosis. Ski‐related novel protein (SnoN) negatively regulates the TGF‐β pathway, but the relationship between SnoN and miR‐21 has not been described in the context of DN. In this study, this association was investigated in vivo (streptozotocin‐induced rat model of diabetes) and in vitro (NRK‐52E model system under high glucose conditions). In both model systems, we observed reduced amounts of the SnoN protein and elevated miR‐21 amounts, indicative of an inverse relationship. These changes in SnoN and miR‐21 amounts were accompanied by reduced E‐cadherin and elevated α‐smooth muscle actin and collagen III levels, consistent with epithelial to mesenchymal transition (EMT). In vitro overexpression of SnoN in NRK‐52E cells downregulated miR‐21 at the transcriptional and posttranscriptional levels and repressed EMT and extracellular matrix (ECM) deposition. In contrast, knockdown of SnoN resulted in miR‐21 upregulation, particularly at the transcriptional level. We further demonstrated that overexpression and inhibition of miR‐21 promoted and suppressed EMT and ECM deposition, respectively, without affecting SnoN levels. Our results indicated that SnoN suppresses the development of DN as well as renal fibrosis by downregulating miR‐21, and therefore represents a novel and promising therapeutic target for DN.

A novel identified circular RNA, circ_0000491, aggravates the extracellular matrix of diabetic nephropathy glomerular mesangial cells through suppressing miR‑101b by targeting TGFβRI

“…TGF-β1/Smad signaling is critical in the process of EMT. Dysregulation of the signaling pathway can contribute to abnormal ECM deposition, causing extensive kidney fibrosis ( 31 , 32 ). In this pathway, TGF-β1 exerts biological effects through binding to type II β-β receptor and subsequently recruits and activates TGFβRI, then the activated TGFβR1 phosphorylates Smad2/3 ( 33 , 34 ).…”

Integrated Analysis of the Mechanisms of Da‐Chai‐Hu Decoction in Type 2 Diabetes Mellitus by a Network Pharmacology Approach

“…In insulin-sensitive tissues such as liver, adipose tissue, and muscle, insulin binds to the α-subunit of the IRTK, causing a conformational change in the RTK, thereby enhancing transphosphorylation between the transmembrane β-subunits further enhances the phosphokinase activity of the RTK, which in turn phosphorylates the insulin receptor substrate (IRS-1). IRS-1 successively combines with PI3K regulatory subunit p85 and catalytic subunit p110, and the activated PI3K produces the second messenger phospholipid inositol (3,4)-triphosphate to promote the activation of AKT. e other type is TLR2, which belongs to Toll-like receptor family and is a very conservative innate immune receptor that can recognize pathogen or injury-related molecular patterns, among which TLR2 is the member that recognizes pathogen-related molecular patterns most.…”

“…Diabetes is one of the three major threats to human health. In the later stage, it will lead to the complications such as cardiovascular and cerebrovascular diseases [2], renal injury [3], retinopathy [4], diabetic foot [5], and neurological disease [6], which are the main reasons for its death rate in diabetic patients. Currently, the incidence of diabetes is rising sharply.…”

Recombinant adiponectin peptide promotes neuronal survival after intracerebral haemorrhage by suppressing mitochondrial and ATF4‐CHOP apoptosis pathways in diabetic mice via Smad3 signalling inhibition

“…Smad3 signalling has been indicated as a central mediator in numerous biological processes, including apoptosis, cell proliferation and energy metabolism. Considerable evidence demonstrates that the activation of Smad3 signalling correlates closely with the severity of metabolic diseases like obesity and diabetes in mice and humans . However, the role played by Smad3 signalling in acute neural injury complicated with diabetes remained unclear.…”