PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation

Xue, Mei; Fang, Ting; Sun, Han‐Dong; Cheng, Ying; Li, Ting; Xu, Chaofei; Tang, Chao; Liu, Xiaohuan; Sun, Bei; Chen, Liming

doi:10.1038/s41419-021-04408-x

Cited by 29 publications

(17 citation statements)

References 48 publications

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“…Among them, in order to verify the quality of rat liver MAM fractions, we performed quality control on different steps of MAM preparation of ZL rat livers ( n = 3) by western blot analysis ( Supplementary Figure S1 ). The distribution trend of six molecules, such as MAM labeled acyl-CoA synthase long chain 4 (ACSL4/FACL4) in different fractions was consistent with the previously published data ( Sonn et al, 2021 ; Xue et al, 2021 ).…”

Section: Resultssupporting

confidence: 91%

Liver mitochondria-associated endoplasmic reticulum membrane proteomics for studying the effects of ZiBuPiYin recipe on Zucker diabetic fatty rats after chronic psychological stress

Zhou²,

Zhan³

et al. 2022

Front. Cell Dev. Biol.

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Type 2 diabetes mellitus (T2DM) is a complex metabolic disease with multiple etiologies, involving both genetic and environmental factors. With changes associated with modern life, increasing attention has been paid to chronic psychological stressors such as work stress. Chronic psychological stress can induce or aggravate diabetes mellitus, and conversely, with the deterioration of T2DM, patients often experience different degrees of depression, anxiety, and other negative emotions. In order to clarify the role of ZiBuPiYin recipe (ZBPYR) in regulating the liver mitochondria-associated endoplasmic reticulum membrane proteome to improve T2DM with chronic psychological stress, differentially expressed proteins (DEPs) were identified among Zucker lean littermates (control group), chronic psychological stress T2DM rats (model group), and ZBPYR administration rats (ZBPYR group) through iTRAQ with LC-MS/MS. Using Mfuzz soft clustering analysis, DEPs were divided into six different clusters. Clusters 1–6 contained 5, 68, 44, 57, 28, and 32 DEPs, respectively. Given that ZBPYR can alleviate T2DM symptoms and affect exploratory behavior during T2DM with chronic psychological stress, we focused on the clusters with opposite expression trends between model:control and ZBPYR:model groups. We screened out the DEPs in clusters 1, 3, and 4, which may be good candidates for the prevention and treatment of T2DM with chronic psychological stress, and further conducted bioinformatics analyses. DEPs were mainly involved in the insulin signaling pathway, oxidative phosphorylation, tricarboxylic acid cycle, amino acid metabolism, lysosome-related processes, and lipid metabolism. This may indicate the pathogenic basis of T2DM with chronic psychological stress and the potential therapeutic mechanism of ZBPYR. In addition, two key proteins, lysosome-associated protein (Lamp2) and tricarboxylic acid cycle-related protein (Suclg1), may represent novel biomarkers for T2DM with chronic psychological stress and drug targets of ZBPYR. Western blot analyses also showed similar expression patterns of these two proteins in liver MAMs of the model and ZBPYR groups.

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Section: Resultssupporting

confidence: 91%

Liver mitochondria-associated endoplasmic reticulum membrane proteomics for studying the effects of ZiBuPiYin recipe on Zucker diabetic fatty rats after chronic psychological stress

Zhou²,

Zhan³

et al. 2022

Front. Cell Dev. Biol.

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“…In contrast, the overexpression of PACS‐2 effectively shielded diabetic kidneys and high glucose‐treated HK‐2 cells from tubular damage. These findings highlight a crucial role for PACS‐2 in the progression of diabetic kidney tubular injury, via stabilization of the MAM (Xue et al, 2021). Now such cross‐organelle stress response can be evaluated by using computational analysis of RNAi signals.…”

Section: Mitochondria‐er Crosstalk During Kidney Diseasesmentioning

confidence: 77%

“…These findings highlight a crucial role for PACS-2 in the progression of diabetic kidney tubular injury, via stabilization of the MAM (Xue et al, 2021). Now such cross-organelle stress response can be evaluated by using computational analysis of RNAi signals.…”

Section: Mitochondria-er Crosstalk During Kidney Diseasesmentioning

confidence: 91%

Epigenetic regulation of mitochondrial‐endoplasmic reticulum dynamics in kidney diseases

Shelke,

Yelgonde,

Kale

et al. 2023

Journal Cellular Physiology

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Kidney diseases are serious health problems affecting >800 million individuals worldwide. The high number of affected individuals and the severe consequences of kidney dysfunction demand an intensified effort toward more effective prevention and treatment. The pathophysiology of kidney diseases is complex and comprises diverse organelle dysfunctions including mitochondria and endoplasmic reticulum (ER). The recent findings prove interactions between the ER membrane and nearly all cell compartments and give new insights into molecular events involved in cellular mechanisms in health and disease. Interactions between the ER and mitochondrial membranes, known as the mitochondria‐ER contacts regulate kidney physiology by interacting with each other via membrane contact sites (MCS). ER controls mitochondrial dynamics through ER stress sensor proteins or by direct communication via mitochondria‐associated ER membrane to activate signaling pathways such as apoptosis, calcium transport, and autophagy. More importantly, these organelle dynamics are found to be regulated by several epigenetic mechanisms such as DNA methylation, histone modifications, and noncoding RNAs and can be a potential therapeutic target against kidney diseases. However, a thorough understanding of the role of epigenetic regulation of organelle dynamics and their functions is not well understood. Therefore, this review will unveil the role of epigenetic mechanisms in regulating organelle dynamics during various types of kidney diseases. Moreover, we will also shed light on different stress origins in organelles leading to kidney disease. Henceforth, by understanding this we can target epigenetic mechanisms to maintain/control organelle dynamics and serve them as a novel therapeutic approach against kidney diseases.

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“…Krzysiak et al (2018) also suggested that the loss of Pacs-2 protected HFD-induced obese mice from both hepatic steatosis and whole-body adiposity by elevating liver SIRT1 activity and its downstream fatty acid oxidation genes. Besides, a recent study showed that the expression of PACS-2 decreased in the kidneys of type 1 and type 2 diabetes mice and Pacs-2 knockout mice with diabetes displayed deterioration of kidney function (Xue et al 2021). However the role of PACS-2 in tubular cells under diabetic condition remains to be further elucidated.…”

Section: Discussionmentioning

confidence: 97%

PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease

Zhao

et al. 2022

Mol Med

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Background Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. Methods Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2−/− mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2−/− mice. Results Diabetic PT-Pacs-2−/− mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2−/− mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. Conclusions PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.

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PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation

Cited by 29 publications

References 48 publications

Liver mitochondria-associated endoplasmic reticulum membrane proteomics for studying the effects of ZiBuPiYin recipe on Zucker diabetic fatty rats after chronic psychological stress

Liver mitochondria-associated endoplasmic reticulum membrane proteomics for studying the effects of ZiBuPiYin recipe on Zucker diabetic fatty rats after chronic psychological stress

Epigenetic regulation of mitochondrial‐endoplasmic reticulum dynamics in kidney diseases

PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease

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