scholarly journals Pathogenesis and Novel Treatment from the Mouse Model of Type 2 Diabetic Nephropathy

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Masako Furukawa ◽  
Tomohito Gohda ◽  
Mitsuo Tanimoto ◽  
Yasuhiko Tomino
Keyword(s):  
Diabetic Nephropathy ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diabetic Model ◽  
Glycation End Products ◽  
Receptor Blockers ◽  
End Stage

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. However, current treatments remain suboptimal. Many factors, such as genetic and nongenetic promoters, hypertension, hyperglycemia, the accumulation of advanced glycation end products (AGEs), dyslipidemia, and albuminuria/proteinuria itself, influence the progression of this disease. It is important to determine the molecular mechanisms and treatment of this disease. The development of diabetes results in the formation of AGEs, oxidative stress, and the activation of the renin-angiotensin-aldosterone system (RAAS) within the kidney, which promotes progressive inflammation and fibrosis, leading to DN and declining renal function. A number of novel therapies have also been tested in the experimental diabetic model, including exercise, inhibitors of the RAAS (angiotensin type 1 receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors), inhibitors of AGE (pyridoxamine), peroxisome proliferator-activated receptor (PPAR)γagonists (pioglitazone), inhibitors of lipid accumulation (statins and eicosapentaenoic acid (EPA)), and the vitamin D analogues. This review summarizes the advances in knowledge gained from our studies and therapeutic interventions that may prevent this disease.

scholarly journals Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity

Circulation ◽  
2004 ◽  
Vol 109 (17) ◽  
pp. 2054-2057 ◽  
Author(s):  
Michael Schupp ◽  
Jürgen Janke ◽  
Ronald Clasen ◽  
Thomas Unger ◽  
Ulrich Kintscher
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Blockers ◽  
Angiotensin Type

Diabetic renal disease

2018 ◽  
Author(s):  
William G. Herrington ◽  
Aron Chakera ◽  
Christopher A. O’Callaghan
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Renal Disease ◽  
Poor Glycaemic Control ◽  
Glycation End Products ◽  
Patients With Diabetes ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is kidney damage occurring as a result of diabetes mellitus. Overt diabetic nephropathy is defined as proteinuria greater than 0.5 g/day. Diabetic nephropathy has a complicated pathogenesis including glomerular hypertension with hyperfiltration and advanced glycation end products. Poor glycaemic control is associated with progression to microalbuminuria and overt diabetic nephropathy. The lifetime risk is fairly equivalent for type 1 and type 2 diabetes mellitus. Early disease is usually asymptomatic. Hyperglycaemia causes an osmotic diuresis and, thus, diabetes can present with polyuria. Hypertension develops with microalbuminuria; oedema indicates abnormal sodium and water retention and, occasionally, the development of nephrotic syndrome. Patients with diabetes, perhaps due to accompanying cardiac disease, are particularly susceptible to fluid overload and uraemic symptoms. End-stage renal disease can occur as early as when the estimated glomerular filtration rate is 15 ml/min 1.73 m−2.

scholarly journals The Rate of Decline of Glomerular Filtration Rate May Not Be Associated with Polymorphism of the PPARγ2 Gene in Patients with Type 1 Diabetes and Nephropathy

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Bingmei Yang ◽  
Hongxin Zhao ◽  
Beverley Ann Millward ◽  
Andrew Glen Demaine
Keyword(s):  
Type 1 Diabetes ◽  
Diabetic Nephropathy ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Baseline Level ◽  
Filtration Rate ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rate Of Decline

The aim of the study was to investigate whether a Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene is associated with the progress of diabetic nephropathy in patients with type 1 diabetes. 197 Caucasian patients with type 1 diabetes and ethnically matched 151 normal healthy controls were genotyped for this polymorphism. Results showed that there were no significant differences in the frequencies of the genotypes and alleles of the polymorphism between groups. Multiple regression analysis in 77 patients demonstrated that the rate of decline in renal function in terms of glomerular filtration rate was significantly correlated to the baseline level of cholesterol (P=0.0014), mean diastolic blood pressure during follow-up period (P=0.019), and baseline level of HbA1c (P=0.022) adjusting for the effect of diabetes duration and gender, but no significant association was found between the polymorphism and the progression of diabetic nephropathy in our studied population. In summary, our results show that the PPARγ2 polymorphism is unlikely to be associated with the development and progression of the diabetic nephropathy in patients with type 1 diabetes. Further studies in different populations may be warranted to confirm our findings as the sample size in our study was relatively small.

scholarly journals Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates

2005 ◽  
Vol 389 (3) ◽  
pp. 913-918 ◽  
Author(s):  
Julio Sevillano ◽  
Inmaculada C. López-Pérez ◽  
Emilio Herrera ◽  
María del Pilar Ramos ◽  
Carlos Bocos
Keyword(s):  
Body Mass ◽  
Control Cell ◽  
Late Pregnancy ◽  
Tissue Growth ◽  
Peroxisome Proliferator ◽  
Pregnant Rats ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akt Phosphorylation ◽  
Insulin Resistant

The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARγ (peroxisome-proliferator-activated receptor γ) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARγ ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition.

scholarly journals RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome

2006 ◽  
Vol 154 (1) ◽  
pp. 159-166 ◽  
Author(s):  
M Messager ◽  
C Carrière ◽  
X Bertagna ◽  
Y de Keyzer
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Ectopic Acth Syndrome ◽  
Pcr Analysis ◽  
Peroxisome Proliferator ◽  
Rt Pcr ◽  
Ectopic Acth ◽  
Peroxisome Proliferator Activated Receptor ◽  
Carcinoid Tumours ◽  
Transcription Factor Genes

Objective: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus. Design: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome. Methods: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms. Results: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in <50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) γ2 were expressed in 50% of the tumours of each group whereas PPARγ1 was expressed in almost every tumour. Conclusions: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.

scholarly journals Growth hormone controls lipolysis by regulation of FSP27 expression

2018 ◽  
Vol 239 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Rita Sharma ◽  
Quyen Luong ◽  
Vishva M Sharma ◽  
Mitchell Harberson ◽  
Brian Harper ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Growth Hormone ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Specific Protein ◽  
Negative Regulator ◽  
Gamma Activity ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative regulator of lipolysis, fat-specific protein 27 (FSP27; aka Cidec) at both the mRNA and protein levels. These effects are mimicked in vivo as transgenic overexpression of GH leads to a reduction of FSP27 expression. Mechanistically, we show GH modulation of FSP27 expression is mediated through activation of both MEK/ERK- and STAT5-dependent intracellular signaling. These two molecular pathways interact to differentially manipulate peroxisome proliferator-activated receptor gamma activity (PPARγ) on the FSP27 promoter. Furthermore, overexpression of FSP27 is sufficient to fully suppress GH-induced lipolysis and insulin resistance in cultured adipocytes. Taken together, these data decipher a molecular mechanism by which GH acutely regulates lipolysis and insulin resistance in adipocytes.

scholarly journals High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

2016 ◽  
Vol 113 (8) ◽  
pp. 2218-2222 ◽  
Author(s):  
Catherine K. Hathaway ◽  
Albert S. Chang ◽  
Ruriko Grant ◽  
Hyung-Suk Kim ◽  
Victoria J. Madden ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Transforming Growth Factor ◽  
Association Studies ◽  
Lipid Peroxides ◽  
Transforming Growth Factor Β1 ◽  
Genome Wide Association Studies ◽  
Diabetic Mice ◽  
Stage Renal Disease ◽  
End Stage

Human genome-wide association studies have demonstrated that polymorphisms in the engulfment and cell motility protein 1 gene (ELMO1) are strongly associated with susceptibility to diabetic nephropathy. However, proof of causation is lacking. To test whether modest changes in its expression alter the severity of the renal phenotype in diabetic mice, we have generated mice that are type 1 diabetic because they have the Ins2Akita gene, and also have genetically graded expression of Elmo1 in all tissues ranging in five steps from ∼30% to ∼200% normal. We here show that the Elmo1 hypermorphs have albuminuria, glomerulosclerosis, and changes in the ultrastructure of the glomerular basement membrane that increase in severity in parallel with the expression of Elmo 1. Progressive changes in renal mRNA expression of transforming growth factor β1 (TGFβ1), endothelin-1, and NAD(P)H oxidase 4 also occur in parallel with Elmo1, as do the plasma levels of cystatin C, lipid peroxides, and TGFβ1, and erythrocyte levels of reduced glutathione. In contrast, Akita type 1 diabetic mice with below-normal Elmo1 expression have reduced expression of these various factors and less severe diabetic complications. Remarkably, the reduced Elmo1 expression in the 30% hypomorphs almost abolishes the pathological features of diabetic nephropathy, although it does not affect the hyperglycemia caused by the Akita mutation. Thus, ELMO1 plays an important role in the development of type 1 diabetic nephropathy, and its inhibition could be a promising option for slowing or preventing progression of the condition to end-stage renal disease.

LncRNA LOC102176306 plays important roles in goat testicular development

Reproduction ◽  
2021 ◽  
Vol 161 (5) ◽  
pp. 523-537
Author(s):  
Shi-Yu An ◽  
Zi-Fei Liu ◽  
El-Samahy M A ◽  
Ming-Tian Deng ◽  
Xiao-Xiao Gao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Complex Iii ◽  
Testicular Development ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Production ◽  
Positive Effects ◽  
And Oxidative Stress

Long ncRNAs regulate a complex array of fundamental biological processes, while its molecular regulatory mechanism in Leydig cells (LCs) remains unclear. In the present study, we established the lncRNA LOC102176306/miR-1197-3p/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) regulatory network by bioinformatic prediction, and investigated its roles in goat LCs. We found that lncRNA LOC102176306 could efficiently bind to miR-1197-3p and regulate PPARGC1A expression in goat LCs. Downregulation of lncRNA LOC102176306 significantly supressed testosterone (T) synthesis and ATP production, decreased the activities of antioxidant enzymes and mitochondrial complex I and complex III, caused the loss of mitochondrial membrane potential, and inhibited the proliferation of goat LCs by decreasing PPARGC1A expression, while these effects could be restored by miR-1197-3p inhibitor treatment. In addition, miR-1197-3p mimics treatment significantly alleviated the positive effects of lncRNA LOC102176306 overexpression on T and ATP production, antioxidant capacity and proliferation of goat LCs. Taken together, lncRNA LOC102176306 functioned as a sponge for miR-1197-3p to maintain PPARGC1A expression, thereby affecting the steroidogenesis, cell proliferation and oxidative stress of goat LCs. These findings extend our understanding of the molecular mechanisms of T synthesis, cell proliferation and oxidative stress of LCs.

Methanol Extract of Mongolian Iris bungei Maxim. Stimulates 3T3-L1 Adipocyte Differentiation

2021 ◽  
Vol 21 (7) ◽  
pp. 3943-3949
Author(s):  
Jaegoo Yeon ◽  
Sung-Suk Suh ◽  
Ui-Joung Youn ◽  
Badamtsetseg Bazarragchaa ◽  
Ganbold Enebish ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Methanol Extract ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor

Iris bungei Maxim. (IB), which is native to China and Mongolia, is used as a traditional medicine for conditions such as inflammation, cancer, and bacterial infections. However, the effects of Iris bungei Maxim. on adipocyte differentiation have not been studied. In the present study, we first demonstrated the molecular mechanisms underlying the adipogenic activity of the methanol extract of Mongolian I. bungei Maxim. (IB). IB significantly enhanced intracellular lipid accumulation and adipocyte differentiation in 3T3-L1 preadipocytes in a concentration-dependent manner. Moreover, IB markedly stimulated the expression of genes related to adipogenesis such as peroxisome proliferator-activated receptor γ, adiponectin, and aP2. In addition, we also observed that IB induces lipogenic genes such as fatty acid synthase, sterol regulatory element binding protein 1c, stearoyl-CoA desaturase, and acetyl-CoA carboxylase. Interestingly IB regulated adipocyte differentiation in both the early and middle stages. Taken together, these adipogenic and lipogenic effects of IB suggest its efficacy for the prevention and/or treatment of type 2 diabetes.

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