scholarly journals Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy

2017 ◽  
Vol 29 (2) ◽  
pp. 434-448 ◽  
Author(s):  
Liad Hinden ◽  
Shiran Udi ◽  
Adi Drori ◽  
Asaad Gammal ◽  
Alina Nemirovski ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Interstitial Fibrosis ◽  
Proximal Tubule Cell ◽  
Functional Changes ◽  
Glucose Transporter 2 ◽  
Cannabinoid 1 Receptor ◽  
Glucose Reabsorption ◽  
Altered Glucose

Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.

scholarly journals SGLT2 inhibition requires reconsideration of fundamental paradigms in chronic kidney disease, ‘diabetic nephropathy’, IgA nephropathy and podocytopathies with FSGS lesions

2020 ◽  
Author(s):  
Hans-Joachim Anders ◽  
Anna Julie Peired ◽  
Paola Romagnani
Keyword(s):  
Chronic Kidney Disease ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Glucose Transporter ◽  
Immunoglobulin A ◽  
Adverse Outcomes ◽  
Glucose Transporter 2 ◽  
Research Activities ◽  
Background Therapy ◽  
Sglt2 Inhibition

Abstract In 2020, the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial first demonstrated that inhibition of the sodium–glucose transporter-2 (SGLT2) with dapagliflozin attenuates the progression of chronic kidney disease (CKD) with proteinuria in patients with or without diabetes at an unprecedented effect size. These results have far-reaching implications for a series of traditional concepts in Nephrology. It now became obvious that CKD with and without diabetes involves a predominant SGLT2-driven pathophysiology compared with the other pathogenic pathways currently under consideration. As SGLT2 inhibition is similarly efficacious in diabetic and non-diabetic CKD with proteinuria, treating CKD rather than ‘diabetic nephropathy’ becomes the central paradigm. Indeed, in older adults with type 2 diabetes, CKD is rather of multifactorial origin. As the DAPA-CKD trial included more patients with immunoglobulin A nephropathy (IgAN) than any of the previous IgAN trials, dual renin-angiotensin/SGLT2 inhibition may become the new standard. The same applies for patients with podocytopathy-related focal segmental glomerulosclerosis lesions. From now on, IgAN and podocytopathy trials without SGLT2 inhibition as background therapy and without glomerular filtration rate decline as primary outcome criterion will be of limited value. These and other potential implications will trigger broad discussions and secondary research activities with conclusions difficult to predict today. However, one is for sure: Nephrology after the DAPA-CKD trial will be not the same as it was before. Finally!

scholarly journals Renal Glycosuria as a Novel Early Sign of Colistin-Induced Kidney Damage in Mice

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Sophia L. Samodelov ◽  
Michele Visentin ◽  
Zhibo Gai ◽  
Stephanie Häusler ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Ex Vivo ◽  
Kidney Injury ◽  
Direct Interaction ◽  
Protein Quantification ◽  
Clinical Markers ◽  
Drug Induced ◽  
Glucose Transporter 2

ABSTRACT The polymyxin colistin represents a last-resort antibiotic for multidrug-resistant infections, but its use is limited by the frequent onset of acute drug-induced kidney injury (DIKI). It is essential to closely monitor kidney function prior to and during colistin treatment in order to pinpoint early signs of injury and minimize long-term renal dysfunction. To facilitate this, a mouse model of colistin-induced nephrotoxicity was used to uncover novel early markers of colistin-induced DIKI. Increased urinary levels of kidney injury molecule-1 (Kim-1) as well as glycosuria were observed in colistin-treated mice, where alterations of established clinical markers of acute kidney injury (serum creatinine and albuminuria) and emerging markers such as cystatin C were inaccurate in flagging renal damage as confirmed by histology. A direct interaction of colistin with renal glucose reabsorption was ruled out by a cis-inhibition assay in mouse brush border membrane vesicles (BBMV). Immunohistochemical examination and protein quantification by Western blotting showed a marked reduction in the protein amount of sodium-glucose transporter 2 (Sglt2), the main kidney glucose transporter, in renal tissue from colistin-treated mice in comparison to that in control animals. Consistently, BBMV isolated from treated mouse kidneys also showed a reduction in ex vivo glucose uptake compared to that in BBMV isolated from control kidneys. These findings support pathology observations of colistin-induced proximal tubule damage at the site of the brush border membrane, where Sglt2 is expressed, and open avenues for the study of glycosuria as a sensitive, specific, and accessible marker of DIKI during colistin therapy.

scholarly journals Transepithelial glucose transport in the small intestine

2020 ◽  
Vol 51 (6) ◽  
pp. 673-686
Author(s):  
Mirela Pavić ◽  
Marija Ljubojević ◽  
Ivona Žura Žaja ◽  
Ivana Prakatur ◽  
Manuela Grčević ◽  
...  
Keyword(s):  
Small Intestine ◽  
Glucose Transport ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Enzymatic Digestion ◽  
Transepithelial Transport ◽  
Facilitated Diffusion ◽  
Glucose Transporter 2 ◽  
Complex Carbohydrates

The duodenum, jejunum and ileum are parts of the small intestine and the sites of the terminal stages of enzymatic digestion, and the majority of nutrient, electrolyte and water absorption. The apical, luminal membrane of the enterocyte is built of numerous microvilli that increase the absorptive surface of the cell. Carbohydrates, in the form of monosaccharides, oligosaccharides and especially polysaccharides, make up the largest quantitative and energetic part of the diet of most animals, including humans. Galactose, fructose and glucose, the final degradation products of polysaccharide and oligosaccharide enzymatic digestion, can be absorbed by enterocytes either by active transport or by facilitated diffusion. In the small intestine, the transepithelial transport of glucose, the most abundant monosaccharide after carbohydrate digestion and the main source of energy, is performed by a specific membrane transporter located in the brush border membrane of the enterocyte, the sodiumglucose cotransporter 1 (SGLT1). While SGLT1 transports glucose across the brush border membrane, a specific basolateral membrane glucose transporter, the sodium-independent glucose transporter 2 (GLUT2), transfers glucose out of the enterocyte down the concentration gradient. The sodium-potassium pump (Na/KATPase), as a sodium and potassium ion transporter, is functionally closely related to the sodium-dependent SGLT1. Na/KATPase is responsible for maintaining the electrochemical gradient of sodium ions, as the driving force for glucose transport via SGLT1. Transepithelial transport of glucose in the small intestine and the differentiation of enterocytes occurs relatively early during the foetal period, allowing glucose to be absorbed from ingested amniotic fluid. Nutrient transport is possible along the whole villus-crypt axis during intrauterine development, while transport shifts toward the villus tip in the mature small intestine. With maturation, glucose transport rates change not only across the villus-crypt axis, but also along the proximodistal axis in the small intestine. The glucose absorption rate shows differences between subunits of the small intestine depending on the age and type of ingested carbohydrates, where complex carbohydrates replace less complex carbohydrates or disaccharides.

Oral polyamine administration modifies the ontogeny of hexose transporter gene expression in the postnatal rat intestine

2007 ◽  
Vol 293 (2) ◽  
pp. G453-G460 ◽  
Author(s):  
G. E. Wild ◽  
L. E. Searles ◽  
K. G. Koski ◽  
L. A. Drozdowski ◽  
J. Begum-Hasan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Basolateral Membrane ◽  
Glucose Transporter 1 ◽  
Sugar Transporters ◽  
Enterocyte Proliferation ◽  
Glucose Transporter 2 ◽  
Postnatal Rats

Gastrointestinal mucosal polyamines influence enterocyte proliferation and differentiation during small intestinal maturation in the rat. Studies in postnatal rats have shown that ornithine decarboxylase (ODC) protein and mRNA peak before the maximal expression of brush-border membrane (BBM) sucrase-isomaltase (SI) and the sugar transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). This study was undertaken to test the hypothesis that the oral administration of spermidine in postnatal rats upregulates the expression of ODC, thereby enhancing the expression of SI and SGLT1 in the brush-border membrane as well as basolateral membrane-facilitative GLUT2 and Na+-K+-ATPase. Northern and Western blot analyses were performed with antibodies and cDNA probes specific for SI, SGLT1, GLUT2, α1- and β1-subunits of Na+-K+-ATPase, and ODC. Postnatal rats fed 6 μmol spermidine daily for 3 days from days 7 to 9 were killed either on postnatal day 10 (Sp10) or day 13 following a 3-day washout period (Sp13). Sp10 rats showed a precocious increase in the abundance of mRNAs for SI, SGLT1, and GLUT2 and Na+-K+-ATPase activity and α1- and β1-isoform gene expression compared with controls. ODC activity and protein and mRNA abundance were also increased in Sp10 animals. The increased expression of these genes was not sustained in Sp13 rats, suggesting that these effects were transient. Thus, 3 days of oral polyamine administration induces the precocious maturation of glucose transporters in the postnatal rat small intestine, which may be mediated by alterations in ODC expression. 1 1 Supplemental material for this article is available online at the American Journal of Physiology-Gastrointestinal and Liver Physiology website.

scholarly journals The apical (hPepT1) and basolateral peptide transport systems of Caco-2 cells are regulated by AMP-activated protein kinase

2010 ◽  
Vol 299 (1) ◽  
pp. G136-G143 ◽  
Author(s):  
Myrtani Pieri ◽  
Helen C. Christian ◽  
Robert J. Wilkins ◽  
C. A. R. Boyd ◽  
David Meredith
Keyword(s):  
Electron Microscopy ◽  
Protein Kinase ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Glucose Transporter ◽  
Peptide Transport ◽  
Transport Systems ◽  
Immunogold Electron Microscopy ◽  
Glucose Transporter 2 ◽  
Amp Activated Protein Kinase

The effect of 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) activation of the AMP-activated protein kinase (AMPK) on the transport of the model radiolabeled dipeptide [3H]-D-Phe-L-Gln was investigated in the human epithelial colon cancer cell line Caco-2. Uptake and transepithelial fluxes of [3H]-D-Phe-L-Gln were carried out in differentiated Caco-2 cell monolayers, and hPepT1 and glucose transporter 2 (GLUT2) protein levels were quantified by immunogold electron microscopy. AICAR treatment of Caco-2 cells significantly inhibited apical [3H]-D-Phe-L-Gln uptake, matched by a decrease in brush-border membrane hPepT1 protein but with a concomitant increase in the facilitated glucose transporter GLUT2. A restructuring of the apical brush-border membrane was seen by electron microscopy. The hPepT1-mediated transepithelial (A-to-B) peptide flux across the Caco-2 monolayers showed no significant alteration in AICAR-treated cells. The electrical resistance in the AICAR-treated monolayers was significantly higher compared with control cells. Inhibition of the sodium/hydrogen exchanger 3 (NHE3) had an additive effect to AICAR, suggesting that the AMPK effect is not via NHE3. Fluorescence measurement of intracellular pH showed no reduction in the proton gradient driving PepT1-mediated apical uptake. The reduction in apical hPepT1 protein and dipeptide uptake after AICAR treatment in Caco-2 cells demonstrates a regulatory effect of AMPK on hPepT1, along with an influence on both the microvilli and tight junction structures. The absence of an associated reduction in transepithelial peptide movement implies an additional stimulatory effect of AICAR on the basolateral peptide transport system in these cells. These results provide a link between the hPepT1 transporter and the metabolic state of this model enterocyte.

scholarly journals Molecular Mechanisms of SGLT2 Inhibitor on Cardiorenal Protection

2020 ◽  
Vol 21 (21) ◽  
pp. 7833
Author(s):  
Yi-Chou Hou ◽  
Cai-Mei Zheng ◽  
Tzung-Hai Yen ◽  
Kuo-Cheng Lu
Keyword(s):  
Diabetes Mellitus ◽  
Vascular Tone ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Clinical Evidence ◽  
Sglt2 Inhibitor ◽  
Cardiac Protection ◽  
Glucose Transporter 2 ◽  
Glucose Reabsorption ◽  
Molecular Aspects

The development of sodium-glucose transporter 2 inhibitor (SGLT2i) broadens the therapeutic strategies in treating diabetes mellitus. By inhibiting sodium and glucose reabsorption from the proximal tubules, the improvement in insulin resistance and natriuresis improved the cardiovascular mortality in diabetes mellitus (DM) patients. It has been known that SGLT2i also provided renoprotection by lowering the intraglomerular hypertension by modulating the pre- and post- glomerular vascular tone. The application of SGLT2i also provided metabolic and hemodynamic benefits in molecular aspects. The recent DAPA-CKD trial and EMPEROR-Reduced trial provided clinical evidence of renal and cardiac protection, even in non-DM patients. Therefore, the aim of the review is to clarify the hemodynamic and metabolic modulation of SGLT2i from the molecular mechanism.

scholarly journals A year in diabetic nephropathy

2021 ◽  
Author(s):  
Jovanna Tsoutsouki ◽  
Tahseen Ahmad Chowdhury
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Nephropathy ◽  
Diabetic Kidney Disease ◽  
Glucose Transporter ◽  
Glucose Transporter 2 ◽  
New Ideas ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
New Guidelines

Whilst 2020 was a year of unique healthcare challenges, in people with type 2 diabetes and diabetic kidney disease (DKD), it was a year of seminal progress. Randomised clinical trials have shown a significant benefit of sodium-glucose transporter-2 inhibitors in patients with DKD, and guidelines now suggest these drugs should be considered in all patients with type 2 diabetes and DKD irrespective of glucose control. Glucagon-like peptide-1 receptor agonists have shown some benefit in reducing progression of albuminuria in DKD, and should also be considered early in the therapeutic pathway. There are new guidelines on the management of post-transplant diabetes, and some new ideas in the management of diabetes in patients on haemodialysis. This article aims to review the year in diabetic nephropathy.

Glucose transporters in animal models of diabetes and hypertension

2006 ◽  
Vol 291 (3) ◽  
pp. F702-F703 ◽  
Author(s):  
Beatriz D’Agord Schaan ◽  
Ubiratan Fabres Machado
Keyword(s):  
Diabetic Nephropathy ◽  
Animal Models ◽  
Glucose Transporter ◽  
Basolateral Membrane ◽  
Glucose Transporters ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Glucose Reabsorption ◽  
Collecting Ducts ◽  
Distal Tubules

Renal tubular glucose reabsorption is mediated by facilitative glucose transporter (GLUT) proteins and energy-dependent sodium glucose luminal transporters. Glucose transport in the diabetic kidney is upregulated and has been implicated in the pathogenesis of progressive diabetic nephropathy. Hyperglycemia, hypertension, and activation of the renin-angiotensin system are believed important in the development of the disease. The present study examines the renal expression of the facilitative glucose transporters GLUT1 and GLUT12 in rat models of diabetic nephropathy. Sprague-Dawley and transgenic (mRen-2)27 rats received either streptozotocin-induced diabetes or vehicle. GLUT12 expression and localization were determined by immunohistochemistry, immunoblotting, in situ hybridization, and confocal immunofluorescence. GLUT1 immunolabeling was detected on the basolateral membrane throughout the nephron. GLUT12 was localized to the distal tubules and collecting ducts. A significant increase in GLUT12 immunolabeling was measured in Ren-2 controls and Ren-2 diabetic animals compared with Sprague-Dawley controls. GLUT12 expression was higher in Ren-2 diabetic compared with Sprague-Dawley diabetic rats. Long-term diabetes resulted in significant increases in GLUT1 levels in the renal proximal tubules and expression was higher in Ren-2 diabetic than Sprague-Dawley diabetic rats. GLUT12 protein was localized to the cytoplasm and to the apical membrane of human and rat distal tubules and collecting ducts. The apical localization of GLUT12 in the distal tubules and collecting ducts suggests that it could contribute to additional glucose reabsorption in the late nephron. Levels of both GLUT1 and GLUT12 are elevated in animal models of hypertension and diabetic nephropathy.

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