Influence of high glucose on mesangial cell-derived exosome composition, secretion and cell communication

Novaes, Antônio da Silva; Borges, Fernanda Teixeira; Maquigussa, Edgar; Varela, Vanessa Araújo; Dias, Maria Assunção Faus da Silva; Boim, Mirian Aparecida

doi:10.1038/s41598-019-42746-1

Cited by 36 publications

(25 citation statements)

References 51 publications

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“…In a similar way, hypoxia also increases the release of MPs from cancer 52 and non-cancer cultured cells such as endothelial cells 53 and human proximal tubular HK-2 cells (the current report). Regarding high-glucose, it has been found to increase the release of exosomes or MPs in several types of cultured renal glomerular cells 27,54,55 Given that hypoxia or high-glucose increase the release of extracellular vesicles in several types of cultured cell it is not surprising that in our experiments the incubation of PTC in HGHD conditions results in increased shedding of MPs. Unfortunately, the mechanisms involved in the increased release of MPs under hypoxia or high-glucose are still at an early stage of comprehension.…”

Section: Discussionmentioning

confidence: 56%

Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

García-Pastor

Benito-Martínez

Moreno‐Manzano

et al. 2019

Sci Rep

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Renal hypoxia and loss of proximal tubular cells (PTC) are relevant in diabetic nephropathy. Hypoxia inhibits hypoxia-inducible factor-1α (HIF-1α) degradation, which leads to cellular adaptive responses through HIF-1-dependent activation of gene hypoxia-responsive elements (HRE). However, the diabetic microenvironment represses the HIF-1/HRE response in PTC. Here we studied the mechanism and consequences of impaired HIF-1α regulation in human proximal tubular HK-2 cells incubated in hyperglycemia. Inhibition at different levels of the canonical pathway of HIF-1α degradation did not activate the HIF-1/HRE response under hyperglycemia, except when proteasome was inhibited. Further studies suggested that hyperglycemia disrupts the interaction of HIF-1α with Hsp90, a known cause of proteasomal degradation of HIF-1α. Impaired HIF-1α regulation in cells exposed to hyperglycemic, hypoxic diabetic-like milieu led to diminished production of vascular endothelial growth factor-A and inhibition of cell migration (responses respectively involved in tubular protection and repair). These effects, as well as impaired HIF-1α regulation, were reproduced in normoglycemia in HK-2 cells incubated with microparticles released by HK-2 cells exposed to diabetic-like milieu. In summary, these results highlight the role of proteasome-dependent mechanisms of HIF-1α degradation on diabetes-induced HK-2 cells dysfunction and suggest that cell-derived microparticles may mediate negative effects of the diabetic milieu on PTC.

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Section: Discussionmentioning

confidence: 56%

Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

García-Pastor

Benito-Martínez

Moreno‐Manzano

et al. 2019

Sci Rep

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“…Somatic gene transfer of the key detoxification enzyme glyoxalase 1 (Glo1) restored the proangiogenic capacity of diabetic EDCs suggesting a means of reversing diabetic cell dysfunction by interfering with the accumulation of reactive dicarbonyls. Interestingly, these changes occurred despite negligible effects on both the paracrine cytokine signature and survival of transplanted cells; suggesting that the fundamental changes wrought by chronic hyperglycemia must alter other cell secreted factors that promote endogenous cardiac repair (such as extracellular vesicles, EVs) 12, 13.…”

Section: Introductionmentioning

confidence: 99%

Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction

Villanueva¹,

Michie²,

Parent³

et al. 2019

Theranostics

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Decades of work have shown that diabetes increases the risk of heart disease and worsens clinical outcomes after myocardial infarction. Because diabetes is an absolute contraindication to heart transplant, cell therapy is increasingly being explored as a means of improving heart function for these patients with very few other options. Given that hyperglycemia promotes the generation of toxic metabolites, the influence of the key detoxification enzyme glyoxalase 1 (Glo1) on chronic hyperglycemia induced heart explant-derived cell (EDC) dysfunction was investigated.Methods: EDCs were cultured from wild type C57Bl/6 or Glo1 over-expressing transgenic mice 2 months after treatment with the pancreatic beta cell toxin streptozotocin or vehicle. The effects of Glo1 overexpression was evaluated using in vitro and in vivo models of myocardial ischemia.Results: Chronic hyperglycemia reduced overall culture yields and increased the reactive dicarbonyl cell burden within EDCs. These intrinsic cell changes reduced the angiogenic potential and production of pro-healing exosomes while promoting senescence and slowing proliferation. Compared to intra-myocardial injection of normoglycemic cells, chronic hyperglycemia attenuated cell-mediated improvements in myocardial function and reduced the ability of transplanted cells to promote new blood vessel and cardiomyocyte growth. In contrast, Glo1 overexpression decreased oxidative damage while restoring both cell culture yields and EDC-mediated repair of ischemic myocardium. The latter was associated with enhanced production of pro-healing extracellular vesicles by Glo1 cells without altering the pro-healing microRNA cargo within.Conclusions: Chronic hyperglycemia decreases the regenerative performance of EDCs. Overexpression of Glo1 reduces dicarbonyl stress and prevents chronic hyperglycemia-induced dysfunction by rejuvenating the production of pro-healing extracellular vesicles.

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“…As such, those EVs generated in response to glomerular or tubular injury might be able to transfer survival and/or damage signals to neighboring or distant cells, promoting diverse biological effects. Several authors have studied the impact of metabolic stimuli, mainly high glucose (HG), in EVs release by glomerular [ 59 , 60 , 61 , 62 , 63 , 64 ] and tubular cells [ 65 ], and in their associated biological activities ( Table 1 ).…”

Section: Biological Effects Of Evs On Renal Cellsmentioning

confidence: 99%

“…Indeed, GMC-derived EVs were similar in size, but not in number, in HG-stimulated cultures compared to controls, exerting different biological effects. As such, the co-incubation of GMCs with mesangial HG-EVs resulted in the production of higher levels of fibronectin, angiotensinogen, renin, Angiotensin II type (AT)1 and AT2 receptors in GMCs, indicating their possible role in kidney cell dysfunction [ 64 ]. In contrast, Barutta et al reported a reduction in the number of GMC-EVs by HG compared to control cultures, which were enriched in miR-145 [ 63 ], while others found no differences in miR-192, -194 or -215 despite HG treatment [ 70 ].…”

Section: Biological Effects Of Evs On Renal Cellsmentioning

confidence: 99%

Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

Saenz-Pipaon

Echeverria

Orbe

et al. 2021

JCM

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Diabetic kidney disease (DKD) is the leading cause of end stage renal disease (ESRD) in developed countries, affecting more than 40% of diabetes mellitus (DM) patients. DKD pathogenesis is multifactorial leading to a clinical presentation characterized by proteinuria, hypertension, and a gradual reduction in kidney function, accompanied by a high incidence of cardiovascular (CV) events and mortality. Unlike other diabetes-related complications, DKD prevalence has failed to decline over the past 30 years, becoming a growing socioeconomic burden. Treatments controlling glucose levels, albuminuria and blood pressure may slow down DKD evolution and reduce CV events, but are not able to completely halt its progression. Moreover, one in five patients with diabetes develop DKD in the absence of albuminuria, and in others nephropathy goes unrecognized at the time of diagnosis, urging to find novel noninvasive and more precise early diagnosis and prognosis biomarkers and therapeutic targets for these patient subgroups. Extracellular vesicles (EVs), especially urinary (u)EVs, have emerged as an alternative for this purpose, as changes in their numbers and composition have been reported in clinical conditions involving DM and renal diseases. In this review, we will summarize the current knowledge on the role of (u)EVs in DKD.

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Influence of high glucose on mesangial cell-derived exosome composition, secretion and cell communication

Cited by 36 publications

References 51 publications

Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

Mechanism and Consequences of The Impaired Hif-1α Response to Hypoxia in Human Proximal Tubular HK-2 Cells Exposed to High Glucose

Glyoxalase 1 Prevents Chronic Hyperglycemia Induced Heart-Explant Derived Cell Dysfunction

Urinary Extracellular Vesicles for Diabetic Kidney Disease Diagnosis

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