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Mette Trauelsen, Elisabeth Rexen Ulven, Siv A Hjorth, Matjaz Brvar, Claudia Monaco, Thomas M Frimurer, Thue W Schwartz
OBJECTIVE: Besides functioning as an intracellular metabolite, succinate acts as a stress-induced extracellular signal through activation of GPR91 (SUCNR1) for which we lack suitable pharmacological tools. METHODS AND RESULTS: Here we first determined that the cis conformation of the succinate backbone is preferred and that certain backbone modifications are allowed for GPR91 activation. Through receptor modeling over the X-ray structure of the closely related P2Y1 receptor, we discovered that the binding pocket is partly occupied by a segment of an extracellular loop and that succinate therefore binds in a very different mode than generally believed...
December 2017: Molecular Metabolism
Julie Gilissen, François Jouret, Bernard Pirotte, Julien Hanson
SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate. According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis...
March 2016: Pharmacology & Therapeutics
Yunyun Zhu, Wenjuan Cong, Lan Shen, Hai Wei, Yuan Wang, Lingyi Wang, Kefeng Ruan, Fei Wu, Yi Feng
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder with systemic complications and has been a worldwide epidemic. Ophiopogon japonicus is a traditional Chinese medicine used to treat diabetes for thousands of years. From our previous work, we know that MDG-1, a water-soluble β-D-fructan polysaccharide from O. japonicas could treat T2DM experimentally. However, MDG-1 is poorly absorbed and its mechanism of action is still unknown. Therefore, a GC TOF/MS-based metabonomic approach in combination with multivariate statistical analysis was performed to investigate the mechanism of MDG-1 in a spontaneous diabetic model...
February 2014: Molecular BioSystems
Mengjie Li, Xufang Wang, Jiye Aa, Weisong Qin, Weibin Zha, Yongchun Ge, Linsheng Liu, Tian Zheng, Bei Cao, Jian Shi, Chunyan Zhao, Xinwen Wang, Xiaoyi Yu, Guangji Wang, Zhihong Liu
Early diagnosis of diabetic nephropathy (DN) is difficult although it is of crucial importance to prevent its development. To probe potential markers and the underlying mechanism of DN, an animal model of DN, the db/db mice, was used and serum and urine metabolites were profiled using gas chromatography/time-of-flight mass spectrometry. Metabolic patterns were evaluated based on serum and urine data. Principal component analysis of the data revealed an obvious metabonomic difference between db/db mice and controls, and db/db mice showed distinctly different metabolic patterns during the progression from diabetes to early, medium, and later DN...
June 1, 2013: American Journal of Physiology. Renal Physiology
Radko Komers
Inhibition of the RAAS (renin-angiotensin-aldosterone system) plays a pivotal role in the prevention and treatment of diabetic nephropathy and a spectrum of other proteinuric kidney diseases. Despite documented beneficial effects of RAAS inhibitors in diabetic patients with nephropathy, reversal of the progressive course of this disorder or at least long-term stabilization of renal function are often difficult to achieve, and many patients still progress to end-stage renal disease. Incomplete inhibition of the RAAS has been postulated as one of reasons for unsatisfactory therapeutic responses to RAAS inhibition in some patients...
May 2013: Clinical Science (1979-)
V V Stel'makh, V K Kozlov, V G Radchenko, A S Nekrasova
Insulin resistance and oxidative stress play an important role in the pathogenetic mechanism of non-alcoholic fatty liver disease. Hepatoprotective therapy that blocks the second phase of pathogenesis (oxidative stress) is a promising modality for the treatment of non-alcoholic steatohepatitis (NACH). An alternative approach is the use of medicines recovering the mitochondrial membrane, lipid bi-layer of the plasma membrane, oxidative phosphorilation, and cellular metabolism. In this context, succinic acid-based remaxol showing antioxidative, antihypoxic and cytoprotective activities can be regarded as a promising metabolic hepatoprotector for the treatment of non-alcoholic fatty liver disease...
2012: Klinicheskaia Meditsina
Nicole Stieger, Kirstin Worthmann, Beina Teng, Stefan Engeli, Anibh M Das, Hermann Haller, Mario Schiffer
Diabetic nephropathy is the most common cause of chronic renal failure in industrialized countries. Depletion of podocytes plays an important role in the progression of diabetic glomerulopathy. Various factors in the diabetic milieu lead to serious podocyte stress driving the cells toward cell cycle arrest (p27(Kip1)), hypertrophy, detachment, and apoptosis. Mitochondria are responsible for oxidative phosphorylation and energy supply in podocytes. Recent studies indicated that mitochondrial dysfunction is a key factor in diabetic nephropathy...
August 2012: Metabolism: Clinical and Experimental
Shanmugam Kondeti Ramudu, Mallikarjuna Korivi, Nishanth Kesireddy, Li-Chen Lee, I-Shiung Cheng, Chia-Hua Kuo, Sathyavelu Reddy Kesireddy
Diabetes is characterized by elevated blood glucose levels and disturbed homeostasis of metabolic enzymes in whole-body. This study aimed to investigate the effect of ginger administration on altered blood glucose levels, intra- and extra-mitochondrial enzymes and tissue injuries in streptozotocin (STZ)-induced diabetic rats. Wistar strain rats (n = 30) were equally divided into 5 groups: normal control (NC), ginger treated (Gt, 200 mg/kg b.w. orally/30 days), diabetic control (DC, 50 mg/kg b.w.), diabetic plus ginger treated (D + Gt) and diabetic plus glibenclamide treated (D + Gli) groups...
April 30, 2011: Chinese Journal of Physiology
Liangcai Zhao, Hongchang Gao, Fulin Lian, Xia Liu, Yongxiang Zhao, Donghai Lin
Elucidation of the metabolic profiling in diabetic nephropathy (DN) rats is of great assistance for understanding the pathogenesis of DN. In this study, ¹H-nuclear magnetic resonance (NMR)-based metabonomics combined with HPLC measurements was used to quantitatively analyze the metabolic changes in urine and kidney extracts from diabetic 2-wk and 8-wk rats induced by streptozotocin (STZ). Pattern recognition analysis of either urine or kidney extracts indicated that the two diabetic groups were separated obviously from the control group, suggesting that the metabolic profiles of the diabetic groups were markedly different from the control...
April 2011: American Journal of Physiology. Renal Physiology
János Peti-Peterdi
Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease. A classic hallmark of diabetes pathology is the activation of the intrarenal renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation has been elusive. Recently, we described the intrarenal localization of the novel metabolic receptor GPR91 and established some of its functions in diabetes. These include the triggering of renin release in early diabetes via both vascular (endothelial) and tubular (macula densa) sites in the juxtaglomerular apparatus as well as the activation of MAP kinases in the distal nephron-collecting duct, which are important signaling mechanisms in diabetic nephropathy (DN) and renal fibrosis...
December 2010: Kidney International
Susumu Ogawa, Takefumi Mori, Kazuhiro Nako, Tsuneo Ishizuka, Sadayoshi Ito
BACKGROUND AND OBJECTIVES: Sarpogrelate has been shown to reduce albuminuria in diabetic nephropathy. For examination of whether this is based on the same mechanisms as angiotensin II receptor blockers or thiazolidinedione, effects of sarpogrelate on atherosclerotic inflammatory molecules and their relations to albuminuria in patients who had diabetes and had already been treated with angiotensin II receptor blockers and with or without thiazolidinedione were examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Forty patients who had diabetes with nephropathy and arteriosclerosis obliterans and had already been treated with angiotensin II receptor blocker (n = 40) were randomly assigned to sarpogrelate (300 mg/d; n = 20) or aspirin group (100 mg/d; n = 20)...
March 2008: Clinical Journal of the American Society of Nephrology: CJASN
Shinya Kobayashi, Minoru Satoh, Tamehachi Namikoshi, Yoshisuke Haruna, Sohachi Fujimoto, Sayaka Arakawa, Norio Komai, Naruya Tomita, Tamaki Sasaki, Naoki Kashihara
BACKGROUND: Serotonin (5-HT) is involved in vascular inflammation and atherosclerogenesis. Serum 5-HT concentrations are elevated in diabetes, and 5-HT is involved in diabetic vasculopathies. Sarpogrelate hydrochloride, a 5-HT2A receptor antagonist, has renoprotective effects, but its effect in diabetic nephropathy is not elucidated. The aim of this study was to examine the effects of sarpogrelate on endothelial dysfunction in rats with streptozotocin (STZ)-induced diabetes. METHODS: Rats with STZ-induced diabetes were either untreated or treated with sarpogrelate (30 mg/kg P...
April 2008: Clinical and Experimental Nephrology
Samir P Patel, Surendra S Katyare
Early and late effects of alloxan diabetes and subsequent treatment with insulin on the temperature kinetics properties of succinate oxidase (SO) activity in rat kidney mitochondria were examined. In diabetic animals SO activity increased significantly and the increase was more pronounced at the late stage. Insulin treatment partially restored SO activity. However, the effect was temperature-dependent. In diabetic animals the energy of activation in the low temperature range (E(L)) increased significantly while that in the high temperature range (E(H)) decreased...
2006: Journal of Membrane Biology
Denyse Thornley-Brown, Xuelei Wang, Jackson T Wright, Otelio S Randall, Edgar R Miller, James P Lash, Jennifer Gassman, Gabriel Contreras, Lawrence J Appel, Lawrence Y Agodoa, Deanna Cheek
BACKGROUND: The African American Study of Kidney Disease and Hypertension was a multicenter trial of African Americans with hypertensive kidney disease randomized to an angiotensin-converting enzyme inhibitor (ramipril), a beta-blocker (metoprolol succinate), or a calcium channel blocker (amlodipine besylate). We compared the incidence of type 2 diabetes mellitus (DM) and the composite outcome of impaired fasting glucose or DM (IFG/DM) for the African American Study of Kidney Disease and Hypertension interventions...
April 10, 2006: Archives of Internal Medicine
Salvatore Cascio, Valeria Solari, Denis J Reen, Prem Puri
PURPOSE: Erythropoietin (EPO) is the principal factor regulating red blood cell production in humans. It has been shown that EPO gradually decreases with the progression of diabetic nephropathy and may be used as a marker of severity of disease. In vitro studies have shown that interleukin-10 (IL-10) acts synergistically with EPO to increase stimulation of erythroid differentiation and proliferation. We evaluate serum levels of EPO and IL-10 in children with reflux nephropathy (RN). MATERIALS AND METHODS: Serum level of EPO and IL-10 were measured in 32 girls and 22 boys with RN, and in 22 boys and 10 girls who served as healthy controls...
October 2004: Journal of Urology
Hsi-Chin Wu, Chao-Hsiang Chang, Ming-May Lai, Cheng-Chieh Lin, Cheng-Chun Lee, Albert Kao
Women with diabetes mellitus (DM) have urinary tract infection (UTI) more often than women without DM. It is unknown, however, what the prevalence and type of renal damage due to UTI is in these women. Therefore, in this study, we compared type 2 DM women with or without UTI history for the prevalence and type of renal damage by technetium-99m dimercapto-succinic acid (Tc-99m DMSA) renal scan. A total of 128 type 2 DM women with or without UTI history received Tc-99m DMSA renal scan were included in this study...
September 2003: Journal of Diabetes and its Complications
Sheila A Doggrell
The main peripheral sources of 5-hydroxytryptamine (5-HT) are as a neurotransmitter and local hormone in the gastrointestinal tract, and stored in circulating platelets and pulmonary neuroepithelial bodies. 5-HT has been shown to have many possible physiological and pathophysiological roles on the cardiovascular and renal systems. Thus, 5-HT may contribute to valvular heart disease, coronary artery disease, pulmonary hypertension, pulmonary embolism, pre-eclampsia, peripheral vascular disease and diabetic nephropathy...
May 2003: Expert Opinion on Investigational Drugs
Chao-Hsiang Chang, Yu-Chien Shiau, Cheng-Chieh Lin, Chia-Hung Kao, Chung-Huei Hsu
UNLABELLED: In this preliminary study, we compared control women and Type 2 diabetes mellitus (DM) women for the prevalence and type of renal damage as revealed by technetium-99m dimercapto-succinic acid (Tc-99m DMSA) renal scan. METHODS: A total of 20 control women and 60 women with Type 2 DM received Tc-99m DMSA renal scan were included in this study. The 60 women with Type 2 DM were separated into three groups: 20 women without UTI history, 20 patients with cystitis histories only, and 20 with pyelonephritis histories...
February 2003: Endocrine Research
Milan Stefek, Narcis Tribulova, Andrej Gajdosik, Alena Gajdosikova
The aim of the present study was to investigate the effects of dietary supplementation with the pyridoindole antioxidant stobadine on histochemical parameters in kidney of streptozotocin-induced diabetic rats. Diabetic male Wistar rats were fed a standard diet or a diet supplemented with stobadine (0.05% w/w) for 24 weeks. The diabetic state was characterized by significantly elevated plasma levels of glucose and glycated hemoglobin, severe reduction of total body weight and relatively enlarged kidneys. Kidney alkaline phosphatase activity was not changed by diabetes...
2002: Acta Histochemica
Takeshi Takahashi, Miyuki Yano, Junko Minami, Tomoko Haraguchi, Naoko Koga, Kiichiro Higashi, Shozo Kobori
We have recently demonstrated that serotonin (5-HT) increases the production of type 4 collagen by cultured human mesangial cells. Here we examined the clinical effects of a 5-HT(A2) receptor antagonist whether it would prevent the development or progression of diabetic nephropathy. We compared the levels of 5-hydroxyindole-3-acetic acid (5-HIAA), the major metabolite of 5-HT, in 24-h urine samples of patients with type 2 diabetes (n=110) and normal subjects (n=40). We then investigated the effects of 24-month treatment with sarpogrelate hydrochloride, a 5-HT(A2) receptor antagonist, on urinary albumin level in 10 type 2 diabetics with microalbuminuria, compared with not treated control group...
November 2002: Diabetes Research and Clinical Practice
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