The endoplasmic reticulum stress and the unfolded protein response in kidney disease: Implications for vascular growth factors

Ricciardi, Carlo Alberto; Gnudi, Luigi

doi:10.1111/jcmm.15999

Cited by 32 publications

(23 citation statements)

References 125 publications

(153 reference statements)

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“…CKD is characterized by elevated inflammation, oxidative stress, and ischemia, which are persistent ER stress inducers that inevitably result in extra accumulation of misfolded or unfolded proteins in the ER. ER stress, including UPR and ERAD, are subsequently initiated to address the abnormally retained proteins [17,47]. Indeed, expressions of ER stress-and UPR-related genes are significantly increased and closely related with kidney function in CKD patients [18].…”

Section: Discussionmentioning

confidence: 99%

“…CKD is characterized by increased endoplasmic reticulum (ER) stress and concomitant with Klotho deficiency, indicating potential interplay between ER stress and Klotho expression [8,[17][18][19]. We previously observed that rats with unilateral ureter obstruction (UUO) induced-renal interstitial fibrosis (RIF) featured both ER stress ignition and Klotho loss, and Klotho replacement treatment repressed renal ER stress and improved their kidney function [20].…”

Section: Introductionmentioning

confidence: 99%

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Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

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Aim: Endoplasmic reticulum-associated degradation (ERAD), which involves degradation of improperly folded proteins retained in the ER, is implicated in various diseases including chronic kidney disease. This study is aimed to determine the role of ERAD in Klotho deficiency of mice and human kidney tubular epithelial cells (HK-2) with renal interstitial fibrosis (RIF). Methods: Following establishment of a mouse RIF model by unilateral ureteral obstruction (UUO), a specific ERAD inhibitor, Eeyarestatin I (EerI), was administered to experimental animals by intraperitoneal injection. Serum and kidney samples were collected for analysis 10 days after operation. Soluble Klotho levels were measured by enzyme-linked immunosorbent assay, while the degree of kidney injury was assessed by renal histopathology. Renal Klotho expression was determined by quantitative real-time PCR, immunohistochemical and western blotting analyses. ERAD and unfolded protein response (UPR) were evaluated by detecting associated components such as Derlin-1, glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4) and protein disulfide isomerase (PDI). HK-2 cells were exposed to transforming growth factor (TGF)-β1 with or without EerI, and expressions of related proteins including Klotho, Derlin-1, GRP78, ATF4 and PDI were determined by western blotting analyses. Results: UUO induced severe kidney injuries and RIF. Klotho expression in both serum and kidney tissue was obviously downregulated, while Derlin-1 was notably upregulated, indicating that ERAD was activated to potentially degrade improperly folded Klotho protein in this model. Intriguingly, treatment with EerI led to significantly increased Klotho expression, especially soluble (functional) Klotho. Furthermore, specific inhibition of ERAD increased expression of GRP78, ATF4 and PDI compared with the UUO group. The consistent results in vitro were also obtained in TGF-β1-treated HK-2 cells exposed to EerI. These observations suggest that UPR was remarkably enhanced in the presence of ERAD inhibition and compensated for excess improperly folded proteins, subsequently contributing to the additional production of mature Klotho protein. Conclusion:ERAD is involved in Klotho deficiency in RIF and its specific inhibition significantly promoted Klotho expression, possibly through enhanced UPR. This may represent a novel regulatory mechanism and new therapeutic target for reversing Klotho deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Li¹,

Kong²,

Liu³

et al. 2022

Int. J. Med. Sci.

View full text Add to dashboard Cite

show abstract

“…Some studies have demonstrated the mechanism by which ER stress participates in various renal fibrosis processes, such as AKI, CKD, and AKI to CKD transition. Studies suggest that ER stress may play different roles in AKI and CKD [ 81 ]. On one hand, transient ER stress was found to trigger adaptive UPR to protect kidney in AKI.…”

Section: Role Of Vegf In Renal Fibrosismentioning

confidence: 99%

“…VEGF activated three UPR signaling pathways, but mainly stimulated PERK and ATF6 to promote cell survival and angiogenesis [ 85 ]. In turn, PERK also stimulated VEGF/VEGFR system [ 81 ]. UPR stimulated the expression of VEGF by ATF4 branch in human umbilical vein endothelial cells [ 86 ].…”

Section: Role Of Vegf In Renal Fibrosismentioning

confidence: 99%

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases

et al. 2022

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Renal fibrosis is the inevitable common end-point of all progressive chronic kidney diseases. The underlying mechanisms of renal fibrosis are complex, and currently there is no effective therapy against renal fibrosis. Renal microvascular rarefaction contributes to the progression of renal fibrosis; however, an imbalance between proangiogenic and antiangiogenic factors leads to the loss of renal microvasculature. Vascular endothelial growth factor (VEGF) is the most important pro-angiogenic factor. Recent studies have unraveled the involvement of VEGF in the regulation of renal microvascular rarefaction and fibrosis via various mechanisms; however, it is not clear whether it has anti-fibrotic or pro-fibrotic effect. This paper reviews the available evidence pertaining to the function of VEGF in the fibrotic process and explores the associated underlying mechanisms. Our synthesis will help identify the future research priorities for developing specialized treatments for alleviating or preventing renal fibrosis. Abbreviation: VEGF: vascular endothelial growth factor; CKD: chronic kidney disease; ESKD: end-stage kidney disease; ER: endoplasmic reticulum; VEGFR: vascular endothelial growth factor receptor; AKI: acute kidney injury; EMT: epithelial-to-mesenchymal transition; HIF: hypoxia-inducible factor; α-SMA: α smooth muscle actin; UUO: unilateral ureteral obstruction; TGF-β: transforming growth factor-β; PMT: pericyte-myofibroblast transition; NO: nitric oxide; NOS: nitric oxide synthase; nNOS: neuronal nitric oxide synthase; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; sGC: soluble guanylate cyclase; PKG: soluble guanylate cyclase dependent protein kinases; UP R: unfolded protein response

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“…Besides, mitochondria play a central regulatory role in endothelial metabolism, closely related to cell proliferation, apoptosis, and nuclear signal transduction ( Qi et al, 2017 ). In addition, mitochondria-associated ER membranes (MAMs), as a novel subcellular structure, have a more profound impact on endothelial function by regulating mitochondrial dynamics, lipid metabolism, and calcium signaling ( Ricciardi and Gnudi, 2020 ). It has been reported that MAMs have multiple roles in diabetic complications ( Wu et al, 2019 ; Cheng et al, 2020 ), but no endothelial cells have been concerned.…”

Section: Introductionmentioning

confidence: 99%

AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice

et al. 2022

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Diabetes is a chronic metabolic disorder that can cause many microvascular and macrovascular complications, including diabetic nephropathy. Endothelial cells exhibit phenotypic and metabolic diversity and are affected by metabolic disorders. Whether changes in endothelial cell metabolism affect vascular endothelial function in diabetic nephropathy remains unclear. In diabetic mice, increased renal microvascular permeability and fibrosis, as well as increased MAMs and PACS2 in renal endothelial cells, were observed. Mice lacking PACS2 improved vascular leakage and glomerulosclerosis under high fat diet. In vitro, PACS2 expression, VE-cadherin internalization, fibronectin production, and Smad-2 phosphorylation increased in HUVECs treated with high glucose and palmitic acid (HGHF). Pharmacological inhibition of AKT significantly reduced HGHF-induced upregulation of PACS2 and p-Smad2 expression. Blocking fatty acid β-oxidation (FAO) ameliorated the impaired barrier function mediated by HGHF. Further studies observed that HGHF induced decreased FAO, CPT1α expression, ATP production, and NADPH/NADP+ ratio in endothelial cells. However, these changes in fatty acid metabolism were rescued by silencing PACS2. In conclusion, PACS2 participates in renal vascular hyperpermeability and glomerulosclerosis by regulating the FAO of diabetic mice. Targeting PACS2 is potential new strategy for the treatment of diabetic nephropathy.

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The endoplasmic reticulum stress and the unfolded protein response in kidney disease: Implications for vascular growth factors

Cited by 32 publications

References 125 publications

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Abnormally decreased renal Klotho is linked to endoplasmic reticulum-associated degradation in mice

Pro- and anti-fibrotic effects of vascular endothelial growth factor in chronic kidney diseases

AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice

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