Long non‑coding RNA TUG1 sponges microRNA‑9 to protect podocytes from high glucose‑induced apoptosis and mitochondrial dysfunction via SIRT1 upregulation

Abstract

Podocyte apoptosis and mitochondrial dysfunction serve a major role in diabetic nephropathy progression. The present study revealed a molecular mechanism regulating podocyte apoptosis and mitochondrial dysfunction. In vitro models were established using conditionally immortalized mouse podocyte clonal cells treated with high glucose (HG). Reverse quantitative-transcription PCR were used to detect gene expression, western blotting and immunofluorescence were used to detect protein expression, Cell Counting Kit-8 was used to detect cell viability and flow cytometry was used to detect cell apoptosis. HG treatment in the mouse podocyte clonal cells downregulated taurine-upregulated gene 1 (TUG1) expression and decreased viability in a dose-dependent manner. In addition, TUG1 knockdown (KD) increased HG-induced apoptosis, while TUG1 overexpression (OE) reduced HG-induced apoptosis in podocytes. HG-induced mitochondrial dysfunction was identified in podocytes, with increased reactive oxygen species levels, decreased complex I/III activity and decreased basal/maximal oxygen consumption rate. TUG1 KD worsened HG-induced mitochondrial dysfunction, and TUG1 OE reversed these effects. At the molecular level, TUG1 was revealed to promote sirtuin 1 (SIRT1) expression by sponging microRNA (miR)-9, and SIRT1 OE reversed the HG-induced apoptosis and mitochondrial dysfunction increased by TUG1 KD. The present data indicated that downregulation of TUG1 induced by HG was associated with HG-induced apoptosis and mitochondrial dysfunction in podocytes, and that TUG1 protected HG-induced podocytes by promoting SIRT1 expression via miR-9 inhibition.

The lncRNA MALAT1 is upregulated in urine of type 1 diabetes mellitus patients with diabetic kidney disease

“…LncRNA TUG1 has been involved in various physiological functions, including cell proliferation, migration and death, and regulation of cell cycle (reviewed in Guo et al, 2020 ). In the context of renal damage, TUG1 seems to be involved in podocyte apoptosis and effacement ( Shen et al, 2019 ; Lei et al , 2022 ), which are involved in glomerular dysfunction and proteinuria. This lncRNA was reported as being downregulated in podocytes of T2DM db/db mice compared to control animals and also in the glomeruli of DKD patients ( Long et al, 2016 ).…”

The role of long non‐coding RNAs in the development of diabetic kidney disease and the involved clinical application

“…140 saponin derived from Astragalus membranaceus, which inhibits the expression of TRAF5 and reduces podocyte apoptosis through the upregulation of TUG1. 144 In conclusion, more research is required to fully understand the therapeutic potential of lncRNAs in DKD.…”

“…In addition, Danggui buxue tang dose‐dependently upregulated the expression of GAS5 in MMCs and inhibited the expression of LN, FN, and col IV by regulating the expression of inhibitor of κB kinase (IKK) and the activity of NF‐κB through GAS5, which, in turn, prevented the effects of DKD by inhibiting the cell proliferation and ECM accumulation in MCs 143 . The therapeutic action of DKD is achieved by Astragaloside IV (AS‐IV), a saponin derived from Astragalus membranaceus, which inhibits the expression of TRAF5 and reduces podocyte apoptosis through the upregulation of TUG1 144 . In conclusion, more research is required to fully understand the therapeutic potential of lncRNAs in DKD.…”

The role of lncRNAs in regulation of DKD and diabetes-related cancer

“…Another work also demonstrated that lncRNA TUG1 reduced accumulation of extracellular matrix by sponging miR-377 and targeting PPARγ in diabetic nephropathy ( 66 ). Moreover, lncRNA TUG1 interacted with miR-9 and upregulated SIRT1, resulting in protection of podocytes from high glucose-triggered apoptosis and mitochondrial dysfunction ( 67 ). Urinary lncRNA TUG1 was positively associated with miR-29a, miR-93 and eGFR in type 2 DM, while lncRNA TUG1 had a negative association with miR-21, miR-124, podocalyxin, NAG and synaptopodin ( 38 ).…”