Renal lipid metabolism and lipotoxicity

Bobulescu, I. Alexandru

doi:10.1097/mnh.0b013e32833aa4ac

Cited by 301 publications

(263 citation statements)

References 108 publications

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“…In addition, lipid deposition has a direct toxic effect on renal function (42). Previous reports suggest that, in addition to proteinuria and hypertension, hyperlipidemia is the third important risk factor for CKD (43).…”

Section: % CI ------------------------------Variablementioning

confidence: 99%

Risk factors associated with secondary hyperparathyroidism in patients with chronic kidney disease

Wei

Lin

Yang

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Secondary hyperparathyroidism (SHPT) is common in patients with chronic kidney disease (CKD), and its development and progression are affected by various factors. The aim of the present study was to identify the risk factors for SHPT in patients with CKD. A retrospective study was performed in 498 patients (305 males and 193 females) with CKD, observed in the The First Hospital of Jilin University between January 2008 and December 2012. The demographic, clinical and laboratory data were collected. Patients were divided into the SHPT group (n=424) with elevated serum parathyroid hormone (PTH) expression levels and the control group (n=74) with normal serum PTH expression levels. Univariate and multivariate regression analyses were employed to explore the risk factors for SHPT. Serum PTH expression levels in women with CKD were significantly higher than in men (P= 0.047). Serum PTH expression levels were positively correlated with the expression levels of serum creatinine (P<0.01), phosphorus (P<0.01), C-reactive protein (P<0.05), triglyceride (P<0.05), cholesterol (P<0.05) and low-density lipoprotein cholesterol (P<0.05), but were negatively correlated with the expression levels of hemoglobin (P<0.05), calcium (P<0.01) and CO 2 combining power (P<0.01) in patients with CKD. Multivariate analysis showed that the serum expression levels of creatinine [µmol/l; odds radio (OR), 1.003; 95% confidence interval (CI), 1.002-1.004; P=0.001] and phosphorus (mmol/l; OR, 2.19; 95% CI, 1.254-3.826; P=0.006) in patients with CKD significantly influenced serum PTH expression levels. The SHPT risk factors include female gender, low calcium, high phosphorus, acidosis, anemia, hypertension, hyperlipidemia and micro-inflammation, with blood phosphorus and creatinine being independent risk factors. IntroductionThe incidence of chronic kidney disease (CKD) is rapidly increasing, posing a serious health problem worldwide. More than 16 million adults are affected by end stage CKD in the USA (1,2). Abnormal serum calcium, phosphorus and parathyroid hormone (PTH) expression levels are common challenges in the management of CKD (3,4). These biochemical abnormalities, together with the dysregulation of vitamin D metabolism and bone turnover, constitute a systemic syndrome termed CKD mineral and bone disorder (CKD-MBD) (5).Secondary hyperparathyroidism (SHPT) is a common complication of patients with CKD, which is characterized by increased blood PTH levels, and abnormal mineral and bone metabolism (6). It is associated with increased morbidity and mortality, and adversely influences the quality of life of patients with CKD (3,6). The incidence of SHPT is reported to increase with the stage of CKD: 40% in stage 3, 70% in stage 4 and >80% in stage 5 (4,7).The kidneys are vital organs regulating calcium and phosphorous homeostasis (8). SHPT is an adaptive pathophysiological process in response to deteriorating renal insufficiency (6). The fundamental mechanism of PTH in kidneys is to suppress the reabsorption of phosphate in the pro...

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Section: % CI ------------------------------Variablementioning

confidence: 99%

Risk factors associated with secondary hyperparathyroidism in patients with chronic kidney disease

Wei

Lin

Yang

et al. 2016

Experimental and Therapeutic Medicine

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“…[1][2][3][4][5] The pathogenesis of obesity and diabetes associated renal disease is multifactorial. [6][7][8][9][10][11][12][13][14] In spite of all the beneficial interventions implemented in diabetic patients, including tight glucose and blood pressure control, renal disease still progresses in most patients. 15,16 Additional treatments able to control pathogenic pathways involved in obesity and diabetic nephropathy (DN) are required.…”

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confidence: 99%

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes

Wang

Edelstein

Gafter

et al. 2015

JASN

157

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Obesity and diabetes mellitus are the leading causes of renal disease. In this study, we determined the regulation and role of the G protein-coupled bile acid receptor TGR5, previously shown to be regulated by high glucose and/or fatty acids, in obesity-related glomerulopathy (ORG) and diabetic nephropathy (DN). Treatment of diabetic db/db mice with the selective TGR5 agonist INT-777 decreased proteinuria, podocyte injury, mesangial expansion, fibrosis, and CD68 macrophage infiltration in the kidney. INT-777 also induced renal expression of master regulators of mitochondrial biogenesis, inhibitors of oxidative stress, and inducers of fatty acid b-oxidation, including sirtuin 1 (SIRT1), sirtuin 3 (SIRT3), and Nrf-1. Increased activity of SIRT3 was evidenced by normalization of the increased acetylation of mitochondrial superoxide dismutase 2 (SOD2) and isocitrate dehydrogenase 2 (IDH2) observed in untreated db/db mice. Accordingly, INT-777 decreased mitochondrial H 2 O 2 generation and increased the activity of SOD2, which associated with decreased urinary levels of H 2 O 2 and thiobarbituric acid reactive substances. Furthermore, INT-777 decreased renal lipid accumulation. INT-777 also prevented kidney disease in mice with dietinduced obesity. In human podocytes cultured with high glucose, INT-777 induced mitochondrial biogenesis, decreased oxidative stress, and increased fatty acid b-oxidation. Compared with normal kidney biopsy specimens, kidney specimens from patients with established ORG or DN expressed significantly less TGR5 mRNA, and levels inversely correlated with disease progression. Our results indicate that TGR5 activation induces mitochondrial biogenesis and prevents renal oxidative stress and lipid accumulation, establishing a role for TGR5 in inhibiting kidney disease in obesity and diabetes.

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“…Obesity-linked dyslipidemia is associated with increased oxidative stress in the kidney (17,18). Conversely, treating dyslipidemia with statins preserves renal function (18,19).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells

et al. 2015

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Background: Statins elicit antioxidant effects independently of their lipid-lowering properties. Heme oxygenase-1 (HO-1) induction may be a part of these pleiotropic effects, which are insufficiently described in the kidney. We hypothesize that simvastatin (SIM) transcriptionally activates HO-1 that protects renal proximal tubule cells from lipotoxic injury. Methods: Impact of SIM on 100 μmol/l oleic acid (OA)-mediated reactive oxygen species (ROS) production and consequent oxidative stress (4-hydroxynonenal (HNE) content) as well as cell injury/apoptosis (lactate dehydrogenase (LDH) release, caspase-3 activation) were determined in cultured renal proximal tubule (NRK52E) cells. Effect of SIM on the HO-1 promoter and its enhancer elements (antioxidant response element (ARE), CCAAT, AP1, and cAMP response element (CRE)) was also determined in reporter luciferase assays. Dominant-negative (dnMEK, M1CREB) and pharmacologic (H89) approaches were used to inhibit activation of extracellular signal regulated kinase (ERK), CREB, and protein kinase A (PKA), respectively. results: SIM dose-dependently activated the HO-1 promoter that was essential for protection against OA-dependent ROS production/oxidative stress and LDH release/caspase-3 activation. We found that the HO-1 promoter was induced through ERK and PKA-dependent activation of the CRE by SIM. conclusion: SIM may protect the kidney from adverse effects of circulating fatty acids by upregulating the antioxidant HO-1, aside from its well-described lipid-lowering effects.o besity is a growing problem among patients of all ages (1,2) that has a variety of effects on different organs including the kidney (3). Adverse effects of obesity are due to increased vascular reactivity, inflammation, and other factors called lipotoxicity (3). Obesity is associated with an elevation of circulating free fatty acids that are responsible for increased oxidative stress and subsequent lipotoxicity (3). Oleic acid (OA), a free fatty acid, is present in high concentration in the plasma of obese individuals (4). Previously, we showed that OA increases production of reactive oxygen species (ROS) that induces oxidative injury in renal proximal tubule cells (5).Statins-such as simvastatin (SIM)-are extensively used to lower dyslipidemia in children (6). Statins are not only lower lipids but also shown to exert "pleiotropic" effects that are not due to their lipid-lowering activity (7). For example, SIM transcriptionally activates the antioxidant HO-1 gene in the liver and NIH3T3 cells (8,9). It is plausible that such antioxidant properties can be used to diminish lipotoxic oxidative stress, caused by obesity. HO-1 induction-dependent renoprotective effects of SIM in a rat model of acute ischemia/reperfusion injury are noted (10) but the underlying mechanism and its potential role in obesity is unknown.Heme oxygenase-1 (HO-1) elicits adaptive responses against oxidative stress in the kidney (11). Oxidative stress transcriptionally induces the HO-1 promoter mostly via the antioxidant respon...

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Renal lipid metabolism and lipotoxicity

Cited by 301 publications

References 108 publications

Risk factors associated with secondary hyperparathyroidism in patients with chronic kidney disease

Risk factors associated with secondary hyperparathyroidism in patients with chronic kidney disease

G Protein-Coupled Bile Acid Receptor TGR5 Activation Inhibits Kidney Disease in Obesity and Diabetes

Simvastatin attenuates oleic acid-induced oxidative stress through CREB-dependent induction of heme oxygenase-1 in renal proximal tubule cells

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