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Proximal tubule

Aurélie Edwards, Muriel Auberson, Suresh K Ramakrishnan, Olivier Bonny
The objective of this study was to investigate theoretically the mechanisms underlying uric acid transport in the proximal tubule (PT) of rat kidneys, and their modulation by factors including Na+ , parathyroid hormone (PTH), Angiotensin II, and SGLT2 inhibitors. To that end, we incorporated the transport of uric acid and its conjugate anion urate in our mathematical model of water and solute transport in the rat PT. The model accounts for parallel urate reabsorption and secretion pathways on apical and basolateral membranes, and their coupling to lactate and alpha-ketoglutarate transport...
February 20, 2019: American Journal of Physiology. Renal Physiology
David Cheng, Linbo Gao, Shan Su, Davit Sargsyan, Renyi Wu, Ilya Raskin, Ah-Ng Kong
Moringa isothiocyanate (MIC-1) is the main active isothiocyanate found in Moringa oleifera, a plant consumed as diet and traditional herbal medicine. Compared to sulforaphane (SFN), MICs are less studied and most work have focused on its anti-inflammatory activity. The purpose of this study is to better understand the Nrf2-ARE antioxidant activity of MIC-1 and its potential in diabetic nephropathy. MIC-1 showed little toxicity from 1.25-5 μM. MIC-1 activated Nrf2-ARE at similar levels to SFN. MIC-1 also increased gene expression of downstream Nrf2 genes NQO1, HO-1, and GCLC...
February 19, 2019: AAPS Journal
Jinzhong Zhang, Jing He, Jennifer L Johnson, Farhana Rahman, Evripidis Gavathiotis, Ana Maria Cuervo, Sergio D Catz
Cystinosis is a lysosomal storage disorder caused by defects in CTNS , the gene that encodes the lysosomal cystine transporter cystinosin. Patients with nephropathic cystinosis are characterized by endocrine defects, defective proximal tubule cell (PTC) function, the development of Fanconi syndrome and, eventually, end-stage renal disease. Kidney disease is developed despite the use of cysteamine, a drug that decreases lysosomal cystine overload but fails to correct overload-independent defects. Chaperone-mediated autophagy (CMA), a selective form of autophagy, is defective in cystinotic mouse fibroblasts, and treatment with cysteamine is unable to correct CMA defects in vivo , but whether the vesicular trafficking mechanisms that lead to defective CMA in cystinosis are manifested in human PTCs is not currently known and whether PTC-specific mechanisms are corrected upon CMA upregulation remains to be elucidated...
2019: Frontiers in Endocrinology
Zhibo Gai, Sophia L Samodelov, Gerd A Kullak-Ublick, Michele Visentin
The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected...
February 12, 2019: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Marika Manolopoulou, Brittany K Matlock, Stellor Nlandu Khodo, Alan J Simmons, Ken S Lau, Melanie Phillips-Mignemi, Alla Ivanova, Catherine E Alford, David K Flaherty, Leslie S Gewin
Flow cytometry studies on injured kidney tubules are complicated by a low yield of nucleated single cells. Furthermore, cell-specific responses such as cell cycle dynamics in vivo has conventionally relied on indirect immunohistochemistry and proximal tubule markers that may be downregulated in injury. We report a new tissue dissociation protocol for kidney with an early fixation step that greatly enhances the yield of single cells. Genetic labeling of the proximal tubule with either the mT/mG "tomato" or the R26Fucci2aR (Fucci) cell cycle reporter mice allows us to follow proximal tubule-specific changes in cell cycle after renal injury...
February 13, 2019: American Journal of Physiology. Renal Physiology
Riobaldo Cintra, Filipe A Moura, Luis Sergio F de Carvalho, Joaquim Barreto, Marcos Tambascia, Roberto Pecoits-Filho, Andrei C Sposito
The prevalence of type 2 diabetes mellitus (T2DM) in the elderly grew sharply over the last decade. Reduced insulin sensitivity and secretory capacity, weight gain, sarcopenia, and elevated adiposity are all common metabolic and body changes in the aging population that favor an increased risk of hypoglycemia, frailty syndrome, falls, and cognitive dysfunction. First line antidiabetic therapy is frequently not safe in older individuals because of its high risk of hypoglycemia and prevalent co-morbid diseases, such as chronic kidney disease, osteoporosis, cardiovascular disease, and obesity...
January 2019: Revista da Associação Médica Brasileira
Theodosios D Filippatos, Angelos Liontos, Ioanna Papakitsou, Moses S Elisaf
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. Aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors-cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), iii) favor the production of ketones, which can act as a "superfuel" in the cardiac and renal tissue (the "thrifty substrate" hypothesis), iv) improve many metabolic variables (the metabolic effects hypothesis), v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), vii) directly decrease the activity of the upregulated in heart failure Na+ -H+ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis)...
February 13, 2019: Postgraduate Medicine
Ankur Sinha, Phone Oo, Muhammad U Asghar, Hira A Cheema, Sanwal S Mehta, Joshua C Leinwand, Kalyana Janga
Topiramate (TMP) is a broad-spectrum anticonvulsant drug used to treat a wide variety of seizure disorders, for migraine prophylaxis, and for many other indications. An important side effect of TMP is metabolic acidosis, which is mediated by renal tubular defects. TMP inhibits carbonic anhydrase, an enzyme that is necessary for acid handling in the proximal renal tubule. Patients can present with asymptomatic serum electrolyte derangements, acute change in mental status, hyperventilation, cardiac arrhythmias, or other sequelae of metabolic acidosis and associated respiratory compensation...
November 26, 2018: Curēus
Julia C Walk, Bruce P Ayati, Sarah A Holstein
Multiple myeloma (MM), a plasma cell cancer, is associated with many health challenges, including damage to the kidney by tubulointerstitial fibrosis. We develop a mathematical model which captures the qualitative behavior of the cell and protein populations involved. Specifically, we model the interaction between cells in the proximal tubule of the kidney, free light chains, renal fibroblasts, and myeloma cells. We analyze the model for steady-state solutions to find a mathematically and biologically relevant stable steady-state solution...
February 11, 2019: Scientific Reports
Masaki Takigawa, Hirofumi Masutomi, Yoshitomo Shimazaki, Tomio Arai, Jaewon Lee, Toshihiro Ishii, Yoshiko Mori, Akihito Ishigami
Vancomycin hydrochloride (VCM) is a glycopeptide antibiotic that is commonly used to eradicate methicillin-resistant gram-positive cocci, despite its nephrotoxic side effects. Elderly people are particularly susceptible to developing VCM-induced nephrotoxicity. However, the precise mechanism by which VCM induces nephrotoxicity in elderly people is not completely understood. Therefore, we investigated VCM-induced nephrotoxicity in mice of different ages. VCM was injected intraperitoneally into mice at 1, 3, 6, 12, and 24 months of age at a dosage of 400 mg/kg body weight for 3 and 14 days...
January 2019: Journal of Toxicologic Pathology
Shinya Kawamoto, Yuji Hidaka, Yu Kaneko, Hideo Misawa, Katsuhiro Nagahori, Atsunori Yoshino, Takamitsu Okamura, Shinichi Ban, Yoshihiko Ueda, Tetsuro Takeda
Light chain proximal tubulopathy is a rare manifestation of monoclonal gammopathy. A 73-year-old Japanese woman was noted to have urinary protein and hypertension on health examination and visited the regional clinic. She was noted to have IgG λ M protein and suspected of multiple myeloma. She was referred to us with massive proteinuria (7.5 g/g creatinine) and Bence Jones proteinuria without renal dysfunction. A renal biopsy revealed no glomerular abnormalities, but a tubular cast was observed partially in tubules without tubular atrophy or a crystalline structure...
February 5, 2019: CEN Case Reports
Danica W Ito, Karen I Hannigan, Debapriya Ghosh, Bing Xu, Silvia G Del Villar, Yang K Xiang, Eamonn J Dickson, Manuel F Navedo, Rose E Dixon
Voltage-dependent L-type CaV 1.2 channels play an indispensable role in cardiac excitation-contraction (EC) coupling. Activation of the β-adrenergic receptor (βAR)/cAMP/PKA signaling pathway leads to enhanced CaV 1.2 activity resulting in increased Ca2+ influx into ventricular myocytes, and a positive inotropic response. CaV 1.2 channels exhibit a clustered distribution along the T-tubule sarcolemma of ventricular myocytes where nanometer proximity between channels permits Ca2+ -dependent cooperative gating behaviour mediated by dynamic, physical, allosteric interactions between adjacent channel C-terminal tails...
February 3, 2019: Journal of Physiology
Lambert Anne-Sophie, Zhukouskaya Volha, Rothenbuhler Anya, Linglart Agnès
X-linked hypophosphatemia (XLH), due to a PHEX gene mutation, is the most common genetic form of rickets and osteomalacia. Manifestations in children consist of rickets, lower-limb bone deformities, bone pain, failure to thrive, dental abscesses, and/or craniostenosis. Adults may present with persistent bone pain, early osteoarthritis, hairline fractures and Looser zones, enthesopathy, and/or periodontitis. Regardless of whether the patient is an infant, child, adolescent or adult, an early diagnosis followed by optimal treatment is crucial to control the clinical manifestations, prevent complications, and improve quality of life...
January 31, 2019: Joint, Bone, Spine: Revue du Rhumatisme
Robert B Cameron, Whitney S Gibbs, Siennah R Miller, Tess V Dupre, Judit K Megyesi, Craig Cano Beeson, Rick G Schnellmann
Acute kidney injury (AKI) is the rapid loss of renal function following an insult and renal proximal tubule cells (RPTC) are central to the pathogenesis of AKI. The β2 adrenergic receptor (β2AR) agonist formoterol accelerates recovery of renal function in mice following ischemia-reperfusion injury (IRI) with associated rescue of mitochondrial proteins. However, the cell type responsible for this recovery remains unknown. The role of RPTC in formoterol-induced recovery of renal function was assessed in a proximal tubule-specific knockout of the β2AR (γGT-Cre:ADRB2Flox/Flox)...
February 1, 2019: Journal of Pharmacology and Experimental Therapeutics
Rakel Nyrén, Elena Makoveichuk, Sandhya Malla, Sander Kersten, Stefan K Nilsson, Madelene Ericsson, Gunilla Olivecrona
Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice some LPL colocalized with the endothelial markers CD31 and GPIHBP1, and could be removed by perfusion with heparin, indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4-/- mice...
January 30, 2019: American Journal of Physiology. Renal Physiology
Austin Chan, Lawrence Park, Lauren F Collins, Curtis Cooper, Michael Saag, Douglas Dieterich, Mark Sulkowski, Susanna Naggie
Background: Concomitant dosing of ledipasvir (LDV) and tenofovir disoproxil fumarate (TDF) results in an increased tenofovir (TFV) area under the curve (AUC). The aim of this study was to examine whether there was a correlation between the renal biomarkers retinol binding protein-4 (RBP-4) and β2 microglobulin (β2M) and tenofovir AUC. Methods: The ION-4 trial enrolled HIV/hepatitis C virus-coinfected patients on nonpharmacologically boosted antiretroviral regimens with TDF-containing backbones...
January 2019: Open Forum Infectious Diseases
Ken Hiratsuka, Toshiaki Monkawa, Tomohiko Akiyama, Yuhki Nakatake, Mayumi Oda, Sravan Kumar Goparaju, Hiromi Kimura, Nana Chikazawa-Nohtomi, Saeko Sato, Keiichiro Ishiguro, Shintaro Yamaguchi, Sayuri Suzuki, Ryuji Morizane, Shigeru B H Ko, Hiroshi Itoh, Minoru S H Ko
The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2+ SALL1+ nephron progenitor cells with 92% efficiency within 2 days...
January 29, 2019: Scientific Reports
Mei-Chen Lo, Ming-Hong Chen, Yu-Ting Hsueh, Yung-Ting Kuo, Horng-Mo Lee
Nε -(carboxymethyl) lysine (CML) plays causal roles in diabetic complications. In the present study, we investigated whether CML-induced HIF-1α accumulation and epithelial-mesenchymal transition (EMT) in HK-2 renal proximal tubular epithelial cells. Treatment with CML-BSA increased reactive oxygen species (ROS) production reduced the mitochondrial membrane potential and induced mitochondrial fragmentation. Pre-treatment of cells with antioxidant, α-lipoic acid, normalised the ROS production and restored the mitochondrial membrane potential...
December 2018: Free Radical Research
Liping Wang, Ning Liu, Xiaoyan Xue, Shujun Zhou
BACKGROUND Acute kidney injury (AKI) involves the renal tubular epithelium. The enhancer of zeste homolog 1 (EZH1) gene has a role in cell development and differentiation. This study aimed to investigate the effect of overexpression of the EZH1 gene on aristolochic acid-induced injury in HK-2 human kidney proximal tubule epithelial cells in vitro. MATERIAL AND METHODS The HK-2 cells were cultured and treated with aristolochic acid and the effects of aristolochic acid-injury were evaluated using a cell counting kit-8 (CCK-8) assay...
January 28, 2019: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Lishan Tan, Xuandi Lai, Mengbi Zhang, Tao Zeng, Youhua Liu, Xiulong Deng, Minzi Qiu, Jiawen Li, Guang Zhou, Meng Yu, Xinran Geng, Jianqiang Hu, Aiqing Li
The renoprotective effects of hypoxia inducible-factor (HIF) activators have been demonstrated by improving renal hypoxia in chronic kidney disease. Cobalt chloride is one of the most widely used HIF activators in biomedicine; however, poor kidney targeting and undesirable side effects greatly limit its clinical applications. Here, we report a novel stimuli-responsive drug release nanoplatform in which glutathione (GSH)-modified Au nanoparticles (GLAuNPs) and Co2+ self-assemble into nanoassemblies (GLAuNPs-Co) through coordination interactions between empty orbitals of Co2+ and lone pairs of GSH...
January 25, 2019: Biomaterials Science
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