A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

Nakatsuka, Atsuko; Yamaguchi, Satoshi; Eguchi, Jun; Kakuta, Shigeru; Iwakura, Yoichiro; Sugiyama, Hitoshi; Wada, Jun

doi:10.1038/s42003-021-01902-y

Cited by 10 publications

(5 citation statements)

References 46 publications

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“…Vaspin exerts multiple beneficial effects in the context of obesity and especially obesity-related comorbidities, as well as liver and vascular inflammation (reviewed in ( 11 , 12 )). Important tools to study and establish the function of this intriguing serpin were vaspin-knockout and vaspin transgenic mouse models ( 10 , 19 , 20 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse

Rapöhn

Elias

Weiner³

et al. 2023

Front. Endocrinol.

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Adipose tissue inflammation and insulin resistance are hallmarks in the development of metabolic diseases resulting from overweight and obesity, such as type 2 diabetes and non-alcoholic fatty liver disease. In obesity, adipocytes predominantly secrete proinflammatory adipokines that further promote adipose tissue dysfunction with negative effects on local and systemic insulin sensitivity. Expression of the serpin vaspin (SERPINA12) is also increased in obesity and type 2 diabetes, but exhibits compensatory roles in inflammation and insulin resistance. This has in part been demonstrated using vaspin-transgenic mice. We here report a new mouse line (h-vaspinTG) with transgenic expression of human vaspin in adipose tissue that reaches vaspin concentrations three orders of magnitude higher than wild type controls (>200 ng/ml). Phenotyping under chow and high-fat diet conditions included glucose-tolerance tests, measurements of energy expenditure and circulating parameters, adipose tissue and liver histology. Also, ex vivo glucose uptake in isolated adipocytes and skeletal muscle was analyzed in h-vaspinTG and littermate controls. The results confirmed previous findings, revealing a strong reduction in diet-induced weight gain, fat mass, hyperinsulinemia, -glycemia and -cholesterolemia as well as fatty liver. Insulin sensitivity in adipose tissue and muscle was not altered. The h-vaspinTG mice showed increased energy expenditure under high fat diet conditions, that may explain reduced weight gain and overall metabolic improvements. In conclusion, this novel human vaspin-transgenic mouse line will be a valuable research tool to delineate whole-body, tissue- and cell-specific effects of vaspin in health and disease.

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Section: Discussionmentioning

confidence: 99%

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse

Rapöhn

Elias

Weiner³

et al. 2023

Front. Endocrinol.

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“…HSPA1L possesses a highly conserved domain structure crucial for protein stabilization, cell proliferation, and apoptosis, as well as cell signal transduction. 20 HSPA1L forms a complex with lamp2 promotes chaperon‐mediated autophagy (CMA), 43 and induces the translocation of Parkin to the damaged mitochondria via P62 inhibition. Since HSPA1L is an important interacting protein of Parkin, 20 MFG‐E8 regulates mitophagy and could be realized through a novel signal pathway (MFG‐E8‐HSPA1L‐Parkin).…”

Section: Discussionmentioning

confidence: 99%

The regulation of MFG‐E8 on the mitophagy in diabetic sarcopenia via the HSPA1L‐Parkin pathway and the effect of D‐pinitol

Zhao,

Meng

et al. 2024

J cachexia sarcopenia muscle

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BackgroundDiabetic sarcopenia is a disease‐related skeletal muscle disorder that causes progressive symptoms. The complete understanding of its pathogenesis is yet to be unravelled, which makes it difficult to develop effective therapeutic strategies. This study investigates how MFG‐E8 affects mitophagy and the protective role of D‐pinitol (DP) in diabetic sarcopenia.MethodsIn vivo, streptozotocin‐induced diabetic SAM‐R1 (STZ‐R1) and SAM‐P8 (STZ‐P8) mice (16‐week‐old) were used, and STZ‐P8 mice were administrated of DP (150 mg/kg per day) for 6 weeks. Gastrocnemius muscles were harvested for histological analysis including transmission electron microscopy. Proteins were evaluated via immunohistochemistry (IHC), immunofluorescence (IF), and western blotting (WB) assay. In vitro, advanced glycation end products (AGEs) induced diabetic and D‐galactose (DG) induced senescent C2C12 models were established and received DP, MFG‐E8 plasmid (Mover)/siRNA (MsiRNA), or 3‐MA/Torin‐1 intervention. Proteins were evaluated by IF and WB assay. Immunoprecipitation (IP) and co‐immunoprecipitation (CO‐IP) were used for hunting the interacted proteins of MFG‐E8.ResultsIn vivo, sarcopenia, mitophagy deficiency, and up‐regulated MFG‐E8 were confirmed in the STZ‐P8 group. DP exerted protective effects on sarcopenia and mitophagy (DP + STZ‐P8 vs. STZ‐P8; all P < 0.01), such as increased lean mass (8.47 ± 0.81 g vs. 7.08 ± 1.64 g), grip strength (208.62 ± 39.45 g vs. 160.87 ± 26.95 g), rotarod tests (109.7 ± 11.81 s vs. 59.3 ± 20.97 s), muscle cross‐sectional area (CSA) (1912.17 ± 535.61 μm2 vs. 1557.19 ± 588.38 μm2), autophagosomes (0.07 ± 0.02 per μm2 vs. 0.02 ± 0.01 per μm2), and cytolysosome (0.07 ± 0.03 per μm2 vs. 0.03 ± 0.01 per μm2). DP down‐regulated MFG‐E8 in both serum (DP + STZ‐P8: 253.19 ± 34.75 pg/mL vs. STZ‐P8: 404.69 ± 78.97 pg/mL; P < 0.001) and gastrocnemius muscle (WB assay. DP + STZ‐P8: 0.39 ± 0.04 vs. STZ‐P8: 0.55 ± 0.08; P < 0.01). DP also up‐regulated PINK1, Parkin and LC3B‐II/I ratio, and down‐regulated P62 in gastrocnemius muscles (all P < 0.01). In vitro, mitophagy deficiency and MFG‐E8 up‐regulation were confirmed in diabetic and senescent models (all P < 0.05). DP and MsiRNA down‐regulated MFG‐E8 and P62, and up‐regulated PINK1, Parkin and LC3B‐II/I ratio to promote mitophagy as Torin‐1 does (all P < 0.05). HSPA1L was confirmed as an interacted protein of MFG‐E8 in IP and CO‐IP assay. Mover down‐regulated the expression of Parkin via the HSPA1L‐Parkin pathway, leading to mitophagy inhibition. MsiRNA up‐regulated the expression of PINK1 via SGK1, FOXO1, and STAT3 phosphorylation pathways, leading to mitophagy stimulation.ConclusionsMFG‐E8 is a crucial target protein of DP and plays a distinct role in mitophagy regulation. DP down‐regulates the expression of MFG‐E8, reduces mitophagy deficiency, and alleviates the symptoms of diabetic sarcopenia, which could be considered a novel therapeutic strategy for diabetic sarcopenia.

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“…Meanwhile, a study on the mechanism of high doses of vitamin E treatment with DKD had shown that high doses of vitamin E could promote lysosomal function and reduce autophagic stress to delay the progression of DKD ( Zhao Y. et al, 2018 ). In addition to this, in order to investigate the role of the vaspin-HSPA1L (heat shock protein family A member 1 like) complex in the development of DKD, the present study made use of patients with obesity-related nephropathy and DKD as well as high-fat and high-glucose-induced mice as models, and then concluded that the vapsin/HSPA1L-mediated pathway played a role in ER stress, impaire autophagy and lysosomal function ( Nakatsuka et al, 2021 ). In summary, the formation of the autolysosome is another key pathway in the autophagic process and is related to the degradation of intracellular metabolites ( Wu M. et al, 2021 ).…”

Section: Dkd and Autophagymentioning

confidence: 99%

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

et al. 2022

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Diabetic kidney disease (DKD) is one of the major public health problems in society today. It is a renal complication caused by diabetes mellitus with predominantly microangiopathy and is a major cause of end-stage renal disease (ESRD). Autophagy is a metabolic pathway for the intracellular degradation of cytoplasmic products and damaged organelles and plays a vital role in maintaining homeostasis and function of the renal cells. The dysregulation of autophagy in the hyperglycaemic state of diabetes mellitus can lead to the progression of DKD, and the activation or restoration of autophagy through drugs is beneficial to the recovery of renal function. This review summarizes the physiological process of autophagy, illustrates the close link between DKD and autophagy, and discusses the effects of drugs on autophagy and the signaling pathways involved from the perspective of podocytes, renal tubular epithelial cells, and mesangial cells, in the hope that this will be useful for clinical treatment.

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A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

Cited by 10 publications

References 46 publications

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse

Overexpressing high levels of human vaspin limits high fat diet-induced obesity and enhances energy expenditure in a transgenic mouse

The regulation of MFG‐E8 on the mitophagy in diabetic sarcopenia via the HSPA1L‐Parkin pathway and the effect of D‐pinitol

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

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