Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress

Park, Min-Jung; Han, Ho Jae; Kim, Dong-Il

doi:10.3390/ijms18071421

Cited by 28 publications

(23 citation statements)

References 31 publications

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“…Indeed, lipotoxicity, in general, and exposure to NEFA, in particular, directly affect mesangial cell functions by activating the intrinsic apoptosis pathway, although the mechanisms of toxicity are not fully elucidated [113][114][115][116]. Furthermore, the use of fenofibrate (PPARα agonist) can prevent lipid-induced toxicity and oxidative stress in glomerular cells by inducing the expression of lipolytic enzymes [117].…”

Section: Lipotoxicity In Renal Cellsmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

189

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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Section: Lipotoxicity In Renal Cellsmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

189

147

View full text Add to dashboard Cite

show abstract

“…Mesangial cells are major components of the glomerular mesangium and primary targets of diabetes; thus, they are intimately involved in glomerulosclerosis [4]. In response to diabetic factors, such as hyperglycemia, oxidative stress, and excess free fatty acids (FFAs), mesangial cells acquire an activated phenotype and then undergo hypertrophy and proliferation or undergo apoptosis, leading to kidney dysfunction [4, 5]. Lipid toxicity is an important mechanism in DN, and mesangial cells are susceptible to lipotoxicity.…”

Section: Introductionmentioning

confidence: 99%

“…ER stress is a physiological and pathological response to excessive accumulation of unfolded or misfolded proteins in the ER. ER stress has been implicated in lipotoxicity-induced apoptosis in multiple cell types, including renal cells [5, 10, 11]. Therefore, antioxidants may exert a protective effect in mesangial cells under palmitate-induced lipotoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of Broussonetia kazinoki Siebold Fruit Extract against Palmitate-Induced Lipotoxicity in Mesangial Cells

Kim

Cha

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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Diabetic nephropathy is one of the most serious complications of diabetes. Lipotoxicity in glomerular mesangial cells is associated with the progression of diabetic nephropathy. Paper mulberry, Broussonetia kazinoki Siebold (BK), has been used in oriental medicine for human health problems. However, to date, the beneficial effect of BK fruit has not been studied. In this study, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against palmitate- (PA-) induced toxicity in mesangial cells. BKFE significantly increased the viability of PA-treated SV40 MES13 cells. BKFE significantly inhibited PA-induced apoptosis and decreased the expression of apoptotic genes, cleaved caspase-3, and cleaved PARP. Moreover, BKFE inhibited the expression of endoplasmic reticulum (ER) stress-related genes, such as BiP, phosphorylated eIF2α, cleaved ATF6, and spliced XBP-1, in PA-treated SV40 MES13 cells. BKFE decreased PA-induced ROS production. In addition, BKFE activated the transcription factor Nrf2 and increased the expression of antioxidant enzymes. However, knockdown of Nrf2 using siRNA suppressed this BKFE-induced increase in antioxidant enzyme expression. Furthermore, the protective effect of BKFE on PA-induced apoptosis was significantly reduced by Nrf2 knockdown. In conclusion, BKFE induced the expression of antioxidant enzymes via activation of Nrf2 and protected against PA-induced lipotoxicity in mesangial cells.

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“…They suggested that these differences in the localization of PRMT1 are due to the variability in cell lines related to the expression of substrate proteins that need to be methylated. Park et al reported that palmitate treatment increases the amount of PRMT1 primarily in the nucleus of glomerular mesangial cells, which is expected to increase the transcription levels of the target genes involved in apoptosis and ER stress 37 . Consistent with their results, our results showed that RANKL increased PRMT1 expression in the nucleus of BMDMs.…”

Section: Discussionmentioning

confidence: 99%

PRMT1 mediates RANKL-induced osteoclastogenesis and contributes to bone loss in ovariectomized mice

et al. 2018

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Protein arginine methylation is a novel form of posttranslational modification mediated by protein arginine methyltransferase (PRMTs). PRMT1, a major isoform of the PRMT family, is responsible for various biological functions, including cellular differentiation. Although the important function that PRMT1 plays in various tissues is being increasingly recognized, its role in receptor activation of NF-κB ligand (RANKL)-induced osteoclastogenesis or osteoporosis has not yet been described. Here, we show that PRMT1 is essential for RANKL-induced osteoclastogenesis in vitro and for bone loss in vivo. RANKL treatment increased the expression of PRMT1 and its nuclear localization in bone marrow-derived macrophages (BMDMs) in a c-Jun N-terminal kinase (JNK)-dependent manner. Silencing PRMT1 attenuated RANKL-induced osteoclastogenesis by decreasing tartrate-resistant acid phosphatase (TRAP)-positive cells and inhibiting F-actin ring formation and bone resorption, which was confirmed in a separate experiment using haploinsufficient cells from PRMT1+/- mice. Our results also revealed that PRMT1 regulates the transcription activity of NF-κB by directly interacting with it in RANKL-treated BMDMs. An in vivo study showed that the haploinsufficiency of PRMT1 reduced the enzyme activity of TRAP and increased the bone mineral density in the metaphysis of ovariectomized (OVX) mice. Finally, treatment with estrogen (E2) downregulated the RANKL-induced expression of PRMT1, suggesting that estrogen may exert an inhibitory effect on osteoclastogenesis by suppressing PRMT1 expression. Our results suggest that PRMT1 plays an important role in the progression of osteoporosis and that it might be a good therapeutic target for postmenopausal osteoporosis.

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Lipotoxicity-Induced PRMT1 Exacerbates Mesangial Cell Apoptosis via Endoplasmic Reticulum Stress

Cited by 28 publications

References 31 publications

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Protective Effects of Broussonetia kazinoki Siebold Fruit Extract against Palmitate-Induced Lipotoxicity in Mesangial Cells

PRMT1 mediates RANKL-induced osteoclastogenesis and contributes to bone loss in ovariectomized mice

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