RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Kim, Soyoung; Park, Samel; Lee, SeongWoo; Lee, Jihye; Lee, Eun Soo; Kim, Miri; Kim, Young-Jo; Kang, Jin Ku; Chung, Choon Hee; Moon, Jong‐Seok; Lee, Eun Young

doi:10.3390/cells10020245

Cited by 13 publications

(9 citation statements)

References 47 publications

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“…As previously mentioned, this study clarified that curcumin treatment could reduce high glucose-induced ROS and RIPK3 production in the podocytes and alleviated the increase of ROS generation after the treatment with RIPK3 inhibitor GSK′872. These findings suggest that ROS generation depends on RIPK3 pathway, which is supported by a recent study investigating lyso-Gb3-induced oxidative stress via RIPK3-dependent pathway and implicating that external stress factors can result in ROS generation via RIPK3-dependent pathway ( Kim et al, 2021 ). In addition, observing a significant recovery of the abnormally increased intracellular ROS expression followed by GSK′872 or NAC treatment confirmed the interdependence between ROS and RIPK3.…”

Section: Discussionsupporting

confidence: 63%

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway

Chung

Lee

Hyun

et al. 2022

Front. Cell Dev. Biol.

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Podocyte loss is well known to play a critical role in the early progression of diabetic nephropathy. A growing number of studies are paying attention to necroptosis, a programmed form of cell necrosis as a mechanism of podocyte loss. Although necroptosis is a recently established concept, the significance of receptor interacting serine/threonine kinase 3 (RIPK3), a gene that encodes for the homonymous enzyme RIPK3 responsible for the progression of necroptosis, is well studied. Curcumin, a natural hydrophobic polyphenol compound responsible for the yellow color of Curcuma longa, has drawn attention due to its antioxidant and anti-inflammatory effects on cells prone to necroptosis. Nonetheless, effects of curcumin on high glucose-induced podocyte necroptosis have not been reported yet. Therefore, this study investigated RIPK3 expression in high glucose-treated podocytes to identify the involvement of necroptosis via the RIPK3 pathway and the effects of curcumin treatment on RIPK3-dependent podocytopathy in a hyperglycemic environment. The study discovered that increased reactive oxygen species (ROS) in renal podocytes induced by high glucose was improved after curcumin treatment. Curcumin treatment also significantly restored the upregulated levels of VEGF, TGF-β, and CCL2 mRNAs and the downregulated level of nephrin mRNA in cultured podocytes exposed to a high glucose environment. High glucose-induced changes in protein expression of TGF-β, nephrin, and CCL2 were considerably reverted to their original levels after curcumin treatment. Increased expression of RIPK3 in high glucose-stimulated podocytes was alleviated by curcumin treatment as well as N-acetyl cysteine (NAC, an antioxidant) or GSK′872 (a RIPK3 inhibitor). Consistent with this, the increased necroptosis-associated molecules, such as RIPK3, pRIPK3, and pMLKL, were also restored by curcumin in high glucose-treated mesangial cells. DCF-DA assay confirmed that such a result was attributed to the reduction of RIPK3 through the antioxidant effect of curcumin. Further observations of DCF-DA-sensitive intracellular ROS in NAC-treated and GSK′872-treated podocyte groups showed a reciprocal regulatory relationship between ROS and RIPK3. The treatment of curcumin and GSK′872 in podocytes incubated with high glucose protected from excessive intracellular superoxide anion production. Taken together, these results indicate that curcumin treatment can protect against high glucose-induced podocyte injuries by suppressing the abnormal expression of ROS and RIPK3. Thus, curcumin might be a potential therapeutic agent for diabetic nephropathy as an inhibitor of RIPK3.

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Section: Discussionsupporting

confidence: 63%

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway

Chung

Lee

Hyun

et al. 2022

Front. Cell Dev. Biol.

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“…Likewise, Kim reported on decreased podocyte survival upon LysoGb3 treatment due to RIPK3-mediated necroptosis (21). Beyond this, GLA deficiency resulted in decreased mTORC1 activity with a subsequent increase in autophagy (22).…”

Section: In Vitro Studiesmentioning

confidence: 94%

The role of tubular cells in the pathogenesis of Fabry nephropathy

Rozenfeld,

Feriozzi,

Braun

2024

Front. Cardiovasc. Med.

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The pathophysiology of Fabry nephropathy (FN) is induced by galactosidase A deficiency with a chronic exposure of glycolipids to every lineage of renal cells. Tissue damage is attributed to the activation of molecular pathways, resulting in tissue fibrosis and chronic kidney disease. Podocytes have been the primary focus in clinical pathophysiological research because of the striking accumulation of large glycolipid deposits observable in histology. Yet, the tubular interstitium makes up a large portion of the whole organ, and therefore, its role must be further considered in pathogenic processes. In this review, we would like to propose Fabry tubulopathy and its ensuing functional effects as the first pathological signs and contributing factors to the development of FN. We will summarize and discuss the current literature regarding the role of tubular cells in Fabry kidney pathophysiology. Starting from clinical and histological evidence, we will highlight the data from animal models and cell cultures outlining the pathophysiological pathways associated with tubular interstitial injury causing renal fibrosis in Fabry nephropathy.

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“…Conditionally immortalized mouse podocytes were kindly provided by Dr. Peter Mundel [ 27 ]. The cells were grown on type I collagen-coated 100-mm dishes (Sigma-Aldrich, Burlington, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation

Sangartit

Jeong

et al. 2022

Endocrinol Metab

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Background: Diabetic nephropathy (DN) is characterized by albuminuria and accumulation of extracellular matrix (ECM) in kidney. Transforming growth factor-β (TGF-β) plays a central role in promoting ECM accumulation. We aimed to examine the effects of EW-7197, an inhibitor of TGF-β type 1 receptor kinase (ALK5), in retarding the progression of DN, both in vivo, using a diabetic mouse model (db/db mice), and in vitro, in podocytes and mesangial cells.Methods: In vivo study: 8-week-old db/db mice were orally administered EW-7197 at a dose of 5 or 20 mg/kg/day for 10 weeks. Metabolic parameters and renal function were monitored. Glomerular histomorphology and renal protein expression were evaluated by histochemical staining and Western blot analyses, respectively. In vitro study: DN was induced by high glucose (30 mM) in podocytes and TGF-β (2 ng/mL) in mesangial cells. Cells were treated with EW-7197 (500 nM) for 24 hours and the mechanism associated with the attenuation of DN was investigated.Results: Enhanced albuminuria and glomerular morphohistological changes were observed in db/db compared to that of the nondiabetic (db/m) mice. These alterations were associated with the activation of the TGF-β signaling pathway. Treatment with EW-7197 significantly inhibited TGF-β signaling, inflammation, apoptosis, reactive oxygen species, and endoplasmic reticulum stress in diabetic mice and renal cells.Conclusion: EW-7197 exhibits renoprotective effect in DN. EW-7197 alleviates renal fibrosis and inflammation in diabetes by inhibiting downstream TGF-β signaling, thereby retarding the progression of DN. Our study supports EW-7197 as a therapeutically beneficial compound to treat DN.

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RIPK3 Contributes to Lyso-Gb3-Induced Podocyte Death

Cited by 13 publications

References 47 publications

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway

Curcumin Blocks High Glucose-Induced Podocyte Injury via RIPK3-Dependent Pathway

The role of tubular cells in the pathogenesis of Fabry nephropathy

EW-7197 Attenuates the Progression of Diabetic Nephropathy in db/db Mice through Suppression of Fibrogenesis and Inflammation

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