Proteasome subunit-α type-6 protein is post-transcriptionally repressed by the microRNA-4490 in diabetic nephropathy

Abstract

A common complication of both type I and type II diabetes is nephropathy, characterized by accumulation of extracellular matrix in the glomerular mesangium. This indicates a central role of mesangial cells in the pathophysiology of diabetic nephropathy. Using the proteomic approach, it was earlier elucidated in a rat model that the proteasome subunit-α type-6 protein (PSMA6) is suppressed in the renal cortex in nephropathic kidney. However, the underlying mechanism effecting suppression of PSMA6 protein in the renal cortex is not yet known. Twenty diabetic patients were enrolled and the expression level of PSMA6 in them was detected by immunohistochemistry. The protein and mRNA expression levels of PSMA6 in NRK-52E cells under high glucose condition were determined by Western blot and quantitative real-time PCR, respectively. Dual luciferase assay was used to detect the relationship of PSMA6 and miR-4490. Our results show that PSMA6 protein is down-regulated in patients with diabetic nephropathy compared with healthy control. Using the NRK-52E cell line cultured under high glucose condition as an in vitro model of diabetic nephropathy, we show that loss of PSMA6 protein expression occured independent of changes the in PSMA6 mRNA expression. We next elucidate that PSMA6 mRNA is post-transcriptionally regulated by the microRNA (miRNA)-4490, whose expression is inversely correlated to PSMA6 protein expression. Using reporter assays we show that PSMA6 is a direct target of the miR-4490. Exogenous manipulation of miR-4490 levels modulated expression of PSMA6, indicating that miR-4490 can be tested as a biomarker for nephropathy in diabetic patients.

Effects of metabolic memory on inflammation and fibrosis associated with diabetic kidney disease: an epigenetic perspective

“…These miRNAs can be divided into T1DN-related miR-NAs, T2DN-related miRNAs, and not-mentioned types. Due to the lack of in-depth research, some miRNAs, such as miR-4490 [94]and miR-423-5p [95], is only limited to in vitro level. In this section, we will mainly focus on the regulatory role of miRNAs on T1DN and T2DN.…”

Shared Blood Transcriptomic Signatures between Alzheimer’s Disease and Diabetes Mellitus

“…Similarly, PSMA6 is a component of the 20S proteasome and is related to both AD and DM [ 47 , 48 ]. Several studies have reported that PSMA6 has a possible role in DM complications, such as myocardial infarction and nephropathy [ 49 , 50 ].…”

Pathophysiology of diabetic kidney disease and autophagy: A review

“…[37,38] In addition, to prevent oxidatively damaged proteins from accumulating during mild oxidative stress, chaperone heat shock proteins refold damaged proteins by recognizing and binding exposed hydrophobic protein sequences, or leave unfolded proteins in a dissolved state to avoid forming multimers with other damaged proteins. [39,40]…”

“…Mitochondria is not only the starting point of oxidative stress, but also the main target organelle of oxidative damage and the repair, regeneration and autophagic degradation of mitochondria to maintain the quality control of mitochondria. [40,41] There is a study about mitochondrial quality control in vitro showed that when mitochondria are damaged, PINK1 exposure on the outer membrane surface increases, where it can activate the ubiquitin ligase of parkin, ubiquitinates the mitochondrial membrane surface protein (Lys63), and binds to the adaptor protein P62 of autophagy, meanwhile it binds to ATG8 on the autophagic vacuole membrane through the microtubule associated protein light chain 3 interacting region (LIR), then promotes recruitment of ubiquitin binding mitophagy receptors to promote capture by the autophagosome. [42] Newly formed autophagic vacuoles firstly associate with acidified endosomes to form autophagosomes and then fuse with lysosomes to form autolysosomes.…”