Increasing triacylglycerol formation and lipid storage by unsaturated lipids protects renal proximal tubules in diabetes

AbstractIn diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). DKD is associated with excessive renal deposition of triacylglycerol (TAG) in lipid droplets (LD). Yet, it is unclear whether LDs play a protective or damaging role and how this might be influenced by dietary patterns. By using a diabetes mouse model, we find here that high fat diet enriched in the unsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTC) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). Mechanistically, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. ER stress is caused by elevated cellular levels of saturated TAG precursors and to higher membrane order in the ER. The resulting cell death is preceded by a transcriptional rewiring of phospholipid metabolism. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and by increasing the total TAG amount. The latter also stimulates the formation of LDs that in turn can release unsaturated lipids upon demand by lipolysis. Our study thus clarifies mechanisms underlying PA-induced cell stress in PTCs and emphasizes the importance of olive oil for the prevention of DKD.

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Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21114054 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4054

Author(s):

Kazuhiko Fukushima ◽

Shinji Kitamura ◽

Kenji Tsuji ◽

Yizhen Sang ◽

Jun Wada

Keyword(s):

Renal Injury ◽

Tubular Damage ◽

Autophagic Flux ◽

Protective Effects ◽

Renal Protection ◽

Proximal Tubular Cells ◽

Tubular Cells ◽

Proximal Tubular ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular

Obesity is supposed to cause renal injury via autophagy deficiency. Recently, sodium glucose co-transporter 2 inhibitors (SGLT2i) were reported to protect renal injury. However, the mechanisms of SGLT2i for renal protection are unclear. Here, we investigated the effect of SGLT2i for autophagy in renal proximal tubular cells (PTCs) on obesity mice. We fed C57BL/6J mice with a normal diet (ND) or high-fat and -sugar diet (HFSD) for nine weeks, then administered SGLT2i, empagliflozin, or control compound for one week. Each group contained N = 5. The urinary N-acetyl-beta-d-glucosaminidase level in the HFSD group significantly increased compared to ND group. The tubular damage was suppressed in the SGLT2i–HFSD group. In electron microscopic analysis, multi lamellar bodies that increased in autophagy deficiency were increased in PTCs in the HFSD group but significantly suppressed in the SGLT2i group. The autophagosomes of damaged mitochondria in PTCs in the HFSD group frequently appeared in the SGLT2i group. p62 accumulations in PTCs were significantly increased in HFSD group but significantly suppressed by SGLT2i. In addition, the mammalian target of rapamycin was activated in the HFSD group but significantly suppressed in SGLT2i group. These data suggest that SGLT2i has renal protective effects against obesity via improving autophagy flux impairment in PTCs on a HFSD.

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Abstract 360: Metformin Confers Cardiac and Renal Protection in Sudden Cardiac Arrest

Circulation ◽

10.1161/circ.142.suppl_4.360 ◽

2020 ◽

Vol 142 (Suppl_4) ◽

Author(s):

Cody A Rutledge ◽

Takuto Chiba ◽

Kevin Redding ◽

Sunder Sims-lucas ◽

Jonathan Elmer ◽

...

Keyword(s):

Cardiac Arrest ◽

Mouse Model ◽

Sudden Cardiac Arrest ◽

Organ Damage ◽

Protective Role ◽

Diabetic Patients ◽

Tubular Damage ◽

Renal Protection ◽

Maximum Serum ◽

Human Pathology

Introduction: Sudden cardiac arrest (SCA) affects over 600,000 Americans yearly with substantial mortality. After resuscitation, multiple system organ damage is common. Metformin has previously demonstrated ischemic protection in cardiac and renal tissues. We retrospectively evaluated kidney damage and cardiac function in a cohort of diabetic SCA patients. We also developed a mouse model of SCA that replicates human pathology and pretreated with metformin to evaluate the molecular changes driving these outcomes. Methods: We performed a retrospective analysis of patients admitted to a single center from 2010 to 2019 after resuscitation from SCA. We included those with a known diabetes prior to arrest. We extracted home medications from nursing and pharmacy medication reconciliations. Our primary exposure of interest was pre-arrest metformin use (vs no or other medications). We compared first day and maximum serum creatinine (SCr) during hospitalization, as well as cardiac ejection fraction (EF) after arrest. To explore the mechanisms underlying these changes, we developed a mouse model of SCA to compare metformin vs non-treated SCA mice. We evaluated EF and renal endpoints including SCr, BUN, and tubular damage 1-day after SCA. Tissues were collected for molecular and histologic studies. Results: We identified 360 diabetic patients of whom 151 (42%) were prescribed metformin at the time of SCA. There were no differences in age, sex, pre-arrest SCr or pre-arrest A1c between metformin and non-metformin treated patients. After SCA, metformin-treated patients had significantly lower initial SCr when compared to non-metformin patients (1.5±0.1 vs 1.7±0.1), 1-day SCr (1.4±0.1 vs 1.7±0.1), max creatinine (1.9±0.1 vs 2.2±0.1 ), and higher EF (49±2 vs 43±2). In the mouse study, pretreatment with metformin group found significantly lower 1-day SCr than non-treated mice (0.40±0.05 vs 1.52±0.22), BUN (64.8±8.2 vs 156.0±39.8), and histologic injury score (0.17±0.71 vs 3.33±0.29), as well as improved 1-day EF (49.6±3.7 vs 38.8±4.5). Conclusions: Our data support a renal- and cardio-protective role for metformin after SCA. Future studies will explore biochemical changes driving protection in the mouse with the goal of discovering translatable therapies.

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mTOR contributes to ER stress and associated apoptosis in renal tubular cells

AJP Renal Physiology ◽

10.1152/ajprenal.00629.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. F267-F274 ◽

Cited By ~ 18

Author(s):

Guie Dong ◽

Yu Liu ◽

Lei Zhang ◽

Shuang Huang ◽

Han-Fei Ding ◽

...

Keyword(s):

Er Stress ◽

Kidney Diseases ◽

Renal Diseases ◽

Therapeutic Effects ◽

Tubular Cells ◽

Tunicamycin Treatment ◽

Renal Tubular Cells ◽

Renal Proximal Tubular Cells ◽

Renal Proximal Tubular ◽

Induced Apoptosis

ER stress has been implicated in the pathogenesis of both acute and chronic kidney diseases. However, the molecular regulation of ER stress in kidney cells and tissues remains poorly understood. In this study, we examined tunicamycin-induced ER stress in renal proximal tubular cells (RPTC). Tunicamycin induced the phosphorylation and activation of PERK and eIF2α within 2 h in RPTC, which was followed by the induction of GRP78 and CHOP. Consistently, tunicamycin also induced apoptosis in RPTC. Interestingly, mTOR was activated rapidly during tunicamycin treatment, as indicated by phosphorylation of both mTOR and p70S6K. Inhibition of mTOR with rapamycin partially suppressed the phosphorylation of PERK and eIF2a and the induction of CHOP and GRP78 induction during tunicamycin treatment. Rapamycin also inhibited apoptosis during tunicamycin treatment and increased cell survival. Collectively, the results suggest that mTOR plays a regulatory role in ER stress, and inhibition of mTOR may have potential therapeutic effects in ER stress-related renal diseases.

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