Renal Protective Effects of Empagliflozin via Inhibition of the EMT Program Associated with Suppression of Aberrant Glycolysis in Proximal Tubules

2019 ◽  
Author(s):  
Jinpeng Li ◽  
Susumu Takagi ◽  
Kyoko Nitta ◽  
Munehiro Kitada ◽  
Swayam P. Srivastava ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Protective Effects

scholarly journals Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

2020 ◽  
Author(s):  
Ayano Kubo ◽  
Teruo Hidaka ◽  
Maiko Nakayama ◽  
Yu Sasaki ◽  
Miyuki Takagi ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Pleiotropic Effects ◽  
Protective Effects ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Dipeptidyl Peptidase 4 ◽  
Anti Oxidant ◽  
Glucagon Like Peptide 1 ◽  
Antigen Antibody

Abstract Background Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. Methods The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. Results DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA and improved the detachment of podocytes. Conclusions DPP-4 activity induces degradation of synaptopodin, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

scholarly journals Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ayano Kubo ◽  
Teruo Hidaka ◽  
Maiko Nakayama ◽  
Yu Sasaki ◽  
Miyuki Takagi ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Pleiotropic Effects ◽  
Protective Effects ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Dipeptidyl Peptidase 4 ◽  
Anti Oxidant ◽  
Glucagon Like Peptide 1 ◽  
Antigen Antibody

Abstract Background Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. Methods The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. Results DPP-4 activity under normal conditions was observed in some Bowman’s capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes. Conclusions DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

scholarly journals Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules

JCI Insight ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Jinpeng Li ◽  
Haijie Liu ◽  
Susumu Takagi ◽  
Kyoko Nitta ◽  
Munehiro Kitada ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Protective Effects

scholarly journals Antioxidant Protection against Pathological Mycotoxins Alterations on Proximal Tubules in Rat Kidney

2011 ◽  
Vol 1 (4) ◽  
pp. 118 ◽  
Author(s):  
Awatef Ali ◽  
Susan Abdu
Keyword(s):  
Serum Creatinine ◽  
Ochratoxin A ◽  
Rat Kidney ◽  
Animal Health ◽  
Periodic Acid ◽  
Relative Weight ◽  
Proximal Tubules ◽  
Protective Effects ◽  
Periodic Acid Schiff ◽  
Ultra Structure

Background: Ochratoxin A (OTA) was one of the mycotoxins and received attention worldwide because of the hazard it posed to human and animal health, where the kidney was the primary target organ for OTA toxicity. In the other hand, dates served as a good source of natural antioxidants and could potentially be considered as a functional food.Methods: The study was performed in the department of biology in King Abdulaziz University. Animals were gavage administrated and divided into four groups: first group received (sodium bicarbonate), second group received (289 µg OTA /kg B.W. /day), third group received (1mg Ajwa/kg B.W. / day) and fourth group received (289 µg OTA /kg B.W./day+ 1mg Ajwa /kg B.W. / day). Serum (creatinine - urea) levels were measured in each group at the time of tissue collection, some biopsies were fixed in 10% buffered formalin solution for light microscopy processing stained with Haematoxylin and Eosin (H& E.), Periodic Acid-Schiff (PAS) and Masson´s Trichrome (M.T.).Other biopsies were immediately collected into electron microscopy processing. Results: After 28 days, a significant decrease in body weight, kidney weight and relative weight was detected in OTA treated group. Also, Serum (creatinine-urea) level were elevated. The normal cyto-architecture of proximal tubules were lost exhibiting damaged bruch border, degenerated, binucleated and karyomegalic cells. The most destructed ultra-structure was the mitochondria which severely swollen with disintegrated membranes. In Ajwa Date extract-group the proximal tubules were normal, whereas in Ajwa date extract + OTA -group the severity of the lesions was significantly reduced. Conclusion: The present results indicated that, Ajwa date have protective effects and ameliorated the lesions of Ochratoxin nepherotoxicity which might lead to kidney failure. Key words: Ochratoxin A., Ajwa date, proximal tubules, light –structure, ultra –structure, biochemical analysis, morphometry.

scholarly journals Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury

2016 ◽  
Vol 310 (5) ◽  
pp. F385-F394 ◽  
Author(s):  
Subhashini Bolisetty ◽  
Amie Traylor ◽  
Reny Joseph ◽  
Abolfazl Zarjou ◽  
Anupam Agarwal
Keyword(s):  
Transgenic Mice ◽  
Proximal Tubule ◽  
Heme Oxygenase ◽  
Kidney Injury ◽  
Cellular Level ◽  
Proximal Tubules ◽  
Heme Oxygenase 1 ◽  
Protective Effects ◽  
Beneficial Effects ◽  
By Products

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. The beneficial effects of HO-1 expression are not merely due to degradation of the pro-oxidant heme but are also credited to the by-products that have potent, protective effects, including antioxidant, anti-inflammatory, and prosurvival properties. This is well reflected in the preclinical animal models of injury in both renal and nonrenal settings. However, excessive accumulation of the by-products can be deleterious and lead to mitochondrial toxicity and oxidative stress. Therefore, use of the HO system in alleviating injury merits a targeted approach. Based on the higher susceptibility of the proximal tubule segment of the nephron to injury, we generated transgenic mice using cre-lox technology to enable manipulation of HO-1 (deletion or overexpression) in a cell-specific manner. We demonstrate the validity and feasibility of these mice by breeding them with proximal tubule-specific Cre transgenic mice. Similar to previous reports using chemical modulators and global transgenic mice, we demonstrate that whereas deletion of HO-1, specifically in the proximal tubules, aggravates structural and functional damage during cisplatin nephrotoxicity, selective overexpression of HO-1 in proximal tubules is protective. At the cellular level, cleaved caspase-3 expression, a marker of apoptosis, and p38 signaling were modulated by HO-1. Use of these transgenic mice will aid in the evaluation of the effects of cell-specific HO-1 expression in response to injury and assist in the generation of targeted approaches that will enhance recovery with reduced, unwarranted adverse effects.

Protection by glycine of proximal tubules from injury due to inhibitors of mitochondrial ATP production

1990 ◽  
Vol 258 (6) ◽  
pp. C1127-C1140 ◽  
Author(s):  
J. M. Weinberg ◽  
J. A. Davis ◽  
M. Abarzua ◽  
T. Kiani ◽  
R. Kunkel
Keyword(s):  
Mitochondrial Function ◽  
Structural Integrity ◽  
Cell Injury ◽  
Buthionine Sulfoximine ◽  
Proximal Tubules ◽  
Atp Depletion ◽  
Protective Effects ◽  
Atp Production ◽  
Carbonyl Cyanide ◽  
Severe Impairment

We have determined whether glycine or glutathione can protect rabbit proximal tubules damaged by chemical inhibitors of oxidative phosphorylation: antimycin A, rotenone, cyanide, oligomycin, or carbonyl cyanide m-chlorophenylhdrazone (CCCP). All the agents severely depleted cell ATP levels within 15 min and caused lethal cell injury, as quantified by lactate dehydrogenase (LDH) release. Glycine and glutathione largely prevented this injury without altering the primary effects of the inhibitors on tubule respiration or the depletion of ATP. Buthionine sulfoximine and 1,3-bis(2-chloroethyl)-1-nitrosourea decreased cell glutathione but did not prevent the protective effects of either glycine or glutathione in tubules treated with rotenone. Protection was sustained during both a 15-min exposure and a 45-min postwash period irrespective of whether the wash removed the agent or mitochondrial function recovered. Cysteine uniquely induced a dramatic recovery of mitochondrial function in tubules washed after treatment with CCCP. These data 1) demonstrate that the cytoprotective effects of glycine previously seen during hypoxia extend to other tubule lesions characterized by severe ATP depletion, 2) emphasize the actions of glycine to preserve cell structural integrity in spite of sustained severe impairment of ATP-generating processes in proximal tubules, and 3) indicate that it is glycine rather than intracellular or extracellular glutathione which mediates protection.

scholarly journals Protective effects of DPP-4 inhibitor on podocyte injury in glomerular diseases

2020 ◽  
Author(s):  
Ayano Kubo ◽  
Teruo Hidaka ◽  
Maiko Nakayama ◽  
Yu Sasaki ◽  
Miyuki Takagi ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Pleiotropic Effects ◽  
Protective Effects ◽  
Crescent Formation ◽  
Glomerular Diseases ◽  
Podocyte Injury ◽  
Dipeptidyl Peptidase 4 ◽  
Anti Oxidant ◽  
Glucagon Like Peptide 1 ◽  
Antigen Antibody

Abstract Background Dipeptidyl peptidase-4 (DPP-4) is a serine protease that inhibits the degradation of glucagon-like peptide 1. DPP-4 inhibitors are used worldwide to treat type 2 diabetes mellitus and were recently shown to have pleiotropic effects such as anti-oxidant, anti-inflammatory, and anti-fibrotic actions. DPP-4 inhibitors improve albuminuria and renal injury including glomerular damage independent of its hypoglycemic effect. Although DPP-4 is mainly expressed in the kidney, the physiological function of DPP-4 remains unclear. Methods The localization of renal DPP-4 activity was determined in human renal biopsy specimens with glycyl-1-prolyl-4-methoxy-2-naphthylamide and the effects of a DPP-4 inhibitor were examined in human cultured podocyte. Results DPP-4 activity under normal conditions was observed in some Bowman's capsular epithelial cells and proximal tubules, but not in the glomerulus. DPP-4 activity was observed in crescent formation in anti-neutrophil myeloperoxidase cytoplasmic antigen antibody nephritis, nodular lesions in diabetic nephropathy, and some podocytes in focal segmental glomerulosclerosis. Notably, the DPP-4 inhibitor saxagliptin suppressed DPP-4 activity in podocytes and the proximal tubules. To assess the effect of DPP-4 inhibitor on podocytes, human cultured podocytes were injured by Adriamycin, which increased DPP-4 activity; this activity was dose-dependently suppressed by saxagliptin. Treatment with saxagliptin maintained the structure of synaptopodin and RhoA. Saxagliptin also improved the detachment of podocytes. Conclusions DPP-4 activity induces degradation of synaptopodin and reduction of RhoA, resulting in destruction of the podocyte cytoskeleton. Saxagliptin may have pleiotropic effects to prevent podocyte injury.

Reduction of Potassium in Kidney Proximal Tubules to Aid in Electron Probe X-Ray Microanalysis of Calcium

1985 ◽  
Vol 43 ◽  
pp. 474-475
Author(s):  
A. LeFurgey ◽  
P. Ingram ◽  
L.J. Mandel
Keyword(s):  
Smooth Muscle ◽  
Proximal Tubule ◽  
Electron Probe ◽  
Clinical Applications ◽  
Proximal Tubules ◽  
Rabbit Kidney ◽  
Target Cells ◽  
X Ray ◽  
Freeze Dried

For quantitative determination of subcellular Ca distribution by electron probe x-ray microanalysis, decreasing (and/or eliminating) the K content of the cell maximizes the ability to accurately separate the overlapping K Kß and Ca Kα peaks in the x-ray spectra. For example, rubidium has been effectively substituted for potassium in smooth muscle cells, thus giving an improvement in calcium measurements. Ouabain, a cardiac glycoside widely used in experimental and clinical applications, inhibits Na-K ATPase at the cell membrane and thus alters the cytoplasmic ion (Na,K) content of target cells. In epithelial cells primarily involved in active transport, such as the proximal tubule of the rabbit kidney, ouabain rapidly (t1/2= 2 mins) causes a decrease2 in intracellular K, but does not change intracellular total or free Ca for up to 30 mins. In the present study we have taken advantage of this effect of ouabain to determine the mitochondrial and cytoplasmic Ca content in freeze-dried cryosections of kidney proximal tubule by electron probe x-ray microanalysis.

Melatonin reduces high levels of lipid peroxidation induced by potassium iodate in porcine thyroid

2019 ◽  
pp. 1-7 ◽  
Author(s):  
Paulina Iwan ◽  
Jan Stepniak ◽  
Malgorzata Karbownik-Lewinska
Keyword(s):  
Lipid Peroxidation ◽  
Oxidative Damage ◽  
Membrane Lipids ◽  
Chemical Properties ◽  
Iodine Concentration ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Protective Effects ◽  
Potassium Iodate ◽  
Hormone Synthesis

Abstract. Iodine is essential for thyroid hormone synthesis. Under normal iodine supply, calculated physiological iodine concentration in the thyroid is approx. 9 mM. Either potassium iodide (KI) or potassium iodate (KIO3) are used in iodine prophylaxis. KI is confirmed as absolutely safe. KIO3 possesses chemical properties suggesting its potential toxicity. Melatonin (N-acetyl-5-methoxytryptamine) is an effective antioxidant and free radical scavenger. Study aims: to evaluate potential protective effects of melatonin against oxidative damage to membrane lipids (lipid peroxidation, LPO) induced by KI or KIO3 in porcine thyroid. Homogenates of twenty four (24) thyroids were incubated in presence of either KI or KIO3 without/with melatonin (5 mM). As melatonin was not effective against KI-induced LPO, in the next step only KIO3 was used. Homogenates were incubated in presence of KIO3 (200; 100; 50; 25; 20; 15; 10; 7.5; 5.0; 2.5; 1.25 mM) without/with melatonin or 17ß-estradiol. Five experiments were performed with different concentrations of melatonin (5.0; 2.5; 1.25; 1.0; 0.625 mM) and one with 17ß-estradiol (1.0 mM). Malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) concentration (LPO index) was measured spectrophotometrically. KIO3 increased LPO with the strongest damaging effect (MDA + 4-HDA level: ≈1.28 nmol/mg protein, p < 0.05) revealed at concentrations of around 15 mM, thus corresponding to physiological iodine concentrations in the thyroid. Melatonin reduced LPO (MDA + 4-HDA levels: from ≈0.97 to ≈0,76 and from ≈0,64 to ≈0,49 nmol/mg protein, p < 0.05) induced by KIO3 at concentrations of 10 mM or 7.5 mM. Conclusion: Melatonin can reduce very strong oxidative damage to membrane lipids caused by KIO3 used in doses resulting in physiological iodine concentrations in the thyroid.

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