Diabetic kidney disease

Nature Reviews Disease Primers, Journal Year: 2015, Volume and Issue: 1(1)

Published: July 30, 2015

Language: Английский

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Mitochondrial Damage and Activation of the STING Pathway Lead to Renal Inflammation and Fibrosis

Cell Metabolism, Journal Year: 2019, Volume and Issue: 30(4), P. 784 - 799.e5

Published: Aug. 29, 2019

Language: Английский

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Mitochondrial dysfunction in diabetic kidney disease

Nature Reviews Nephrology, Journal Year: 2018, Volume and Issue: 14(5), P. 291 - 312

Published: Feb. 19, 2018

Language: Английский

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Epigenetics and epigenomics in diabetic kidney disease and metabolic memory

Nature Reviews Nephrology, Journal Year: 2019, Volume and Issue: 15(6), P. 327 - 345

Published: March 20, 2019

Language: Английский

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Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Nature Medicine, Journal Year: 2017, Volume and Issue: 23(6), P. 753 - 762

Published: April 24, 2017

Language: Английский

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Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

Journal of Clinical Investigation, Journal Year: 2014, Volume and Issue: 125(1), P. 141 - 156

Published: Nov. 20, 2014

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides distribute kidney inhibit miR-21 function when administered subcutaneously evaluated therapeutic potential these anti-miR-21 chronic disease. In a murine model Alport nephropathy, did not produce any adverse effects resulted substantially milder disease, with minimal albuminuria dysfunction, compared vehicle-treated mice. dramatically improved survival mice reduced histological end points, glomerulosclerosis, interstitial fibrosis, tubular injury, inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity downstream signaling glomerular, tubular, cells. Moreover, mitochondrial function, which production thus preserved functions. Inhibition was protective against TGF-β-induced fibrogenesis inflammation glomerular cells, likely as result PPARα/RXR function. Together, results demonstrate inhibition represents strategy nephropathy.

Language: Английский

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Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

Nature Reviews Nephrology, Journal Year: 2016, Volume and Issue: 12(7), P. 426 - 439

Published: May 3, 2016

Language: Английский

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The tubular hypothesis of nephron filtration and diabetic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 16(6), P. 317 - 336

Published: March 9, 2020

Language: Английский

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Molecular mechanisms and therapeutic targets for diabetic kidney disease

Kidney International, Journal Year: 2022, Volume and Issue: 102(2), P. 248 - 260

Published: June 3, 2022

Diabetic kidney disease has a high global burden and substantially increases the risk of failure cardiovascular events. Despite treatment, there is substantial residual progression with existing therapies. Therefore, an urgent need to better understand molecular mechanisms driving diabetic help identify new therapies that slow reduce associated risks. initiated by diabetes-related disturbances in glucose metabolism, which then trigger other metabolic, hemodynamic, inflammatory, fibrotic processes contribute progression. This review summarizes evidence on drivers onset progression, focusing inflammatory mediators—factors are largely unaddressed as primary treatment targets for increasing supporting key roles pathophysiology disease. Results from recent clinical trials highlight promising drug therapies, well role dietary strategies, treating Chronic (CKD), characterized albuminuria, low estimated glomerular filtration rate (eGFR), or both,1GBD Kidney Disease CollaborationGlobal, regional, national chronic disease, 1990-2017: systematic analysis Global Burden Study 2017.Lancet. 2020; 395: 709-733Abstract Full Text PDF PubMed Scopus (1156) Google Scholar affect over 840 million people worldwide.2Jager K.J. Kovesdy C. Langham R. et al.A single number advocacy communication-worldwide more than 850 individuals have diseases.Kidney Int. 2019; 96: 1048-1050Abstract (DKD), damage due diabetes, leading attributable cause CKD, occurring approximately 40% type 2 diabetes (T2D) 30% those 1 (T1D).1GBD Scholar,3Alicic R.Z. Rooney M.T. Tuttle K.R. disease: challenges, progress, possibilities.Clin J Am Soc Nephrol. 2017; 12: 2032-2045Crossref (753) The DKD expected increase parallel rise prevalence,3Alicic projected nearly 50%, 537 783 people, next 24 years.4International Diabetes FederationIDF Atlas.10th ed. International Federation, 2021Google improve diagnosis management DKD, including target related (CV) risk.1GBD Mechanisms can be broadly classified fibrotic.3Alicic Scholar,5Pérez-Morales R.E. Del Pino M.D. Valdivielso J.M. al.Inflammation disease.Nephron. 143: 12-16Crossref (57) Scholar,6Mora-Fernández Domínguez-Pimentel V. de Fuentes M.M. al.Diabetic physiology therapeutics.J Physiol. 2014; 592: 3997-4012Crossref (99) In this review, current understanding drive pathogenesis presented basis advancing therapeutic interventions. Hyperglycemia induces hyperfiltration hypertension, hemodynamic long been recognized initiate propagate diabetes.3Alicic Glomerular exacerbated levels amino acids, example, after protein overfeeding, hormonal changes poor glycemic control, level glucagon.7Rhee C.M. Kalantar-Zadeh K. Novel approaches hypoglycemia burnt-out disease.Curr Opin Nephrol Hypertens. 2022; 31: 72-81Crossref (0) Scholar, 8Tuttle Bruton J.L. Effect insulin therapy renal response acids hypertrophy non-insulin-dependent diabetes.Kidney 1992; 42: 167-173Abstract 9Tuttle Perusek M.C. al.Effect strict control enlargement insulin-dependent mellitus.N Engl Med. 1991; 324: 1626-1632Crossref (142) 10Tuttle Puhlman M.E. Cooney S.K. Short R.A. Effects glucagon hemodynamics diabetes.Am Physiol Renal 2002; 282: F103-F112Crossref These circulating mediators primarily act perfusion through afferent arteriole dilation.3Alicic Scholar,8Tuttle addition, activation renin angiotensin system local hyperfiltration. Angiotensin II production within constricts efferent arteriole, thereby, contributes higher pressure. stimulates expression proinflammatory profibrotic via barotrauma also direct cellular effects.3Alicic Scholar,10Tuttle sodium-glucose cotransporter-2 (SGLT2) now another important modulator hemodynamics. It expressed luminal surface epithelial cells proximal convoluted tubule responsible 90% filtered reabsorption.11Alicic Neumiller J.J. Johnson E.J. al.Sodium-glucose cotransporter inhibition disease.Diabetes. 68: 248-257Crossref (55) Scholar,12Vallon Gerasimova M. Rose M.A. al.SGLT2 inhibitor empagliflozin reduces growth albuminuria proportion hyperglycemia prevents Akita mice.Am 306: F194-F204Crossref (318) hyperglycemic conditions, SGLT2 activity adaptation reclaim urine, but maladaptive consequence worsening hyperglycemia.11Alicic Scholar,13Heerspink H.J. Perkins B.A. Fitchett D.H. al.Sodium inhibitors mellitus: effects, potential mechanisms, applications.Circulation. 2016; 134: 752-772Crossref Therapeutically, lowers blood decreasing reabsorption at resulting glucosuria.13Heerspink restore tubuloglomerular feedback distal delivery sodium chloride macula densa, where solute generates adenosine by-product triphosphate utilization. Adenosine acts paracrine manner enhance arteriolar vasoconstriction, suppress release juxtaglomerular cells, perhaps constriction.11Alicic Scholar,14Kidokoro Cherney D.Z.I. Bozovic A. al.Evaluation function mice using vivo imaging.Circulation. 140: 303-315Crossref (124) 15Ortiz-Capisano Atchison D.K. Harding P. al.Adenosine inhibits A1 receptor-TRPC-mediated pathway.Am 2013; 305: F1209-F1219Crossref 16Heerspink H.J.L. Perco Mulder S. al.Canagliflozin inflammation fibrosis biomarkers: mechanism action beneficial effects disease.Diabetologia. 62: 1154-1166Crossref (145) 17Vallon Thomson S.C. tubular hypothesis nephron disease.Nat Rev 16: 317-336Crossref (102) relative balance between constriction may vary age. physiological studies humans normal GFR, younger T1D demonstrated constriction, whereas older T2D had dilation.18van Bommel E.J.M. Lytvyn Y. al.Renal hyperfiltering function.Kidney 97: 631-635Abstract (17) Irrespective precise vasoregulatory whole, restoration hypertension and, hyperfiltration.14Kidokoro Scholar,18van prompts series intracellular promote (Figure 1).3Alicic Scholar,19Zhao L. Zou Liu F. Transforming factor-beta1 disease.Front Cell Dev Biol. 8: 187Crossref (34) Scholar,20Reidy Kang H.M. Hostetter T. Susztak Molecular disease.J Clin Invest. 124: 2333-2340Crossref (448) Altered metabolism advanced glycation end products (AGEs), reactive oxygen species, kinase C Janus (JAK)-signal transducer activator transcription (STAT) pathways.20Reidy Podocytes exposed AGE nuclear factor κB–associated upregulation messenger RNA variety much 25-fold.21Pichler Afkarian Dieter B.P. Immunity translating biomarkers targets.Am 312: F716-F731Crossref (108) Scholar,22Anderberg R.J. Meek R.L. Hudkins K.L. al.Serum amyloid A podocytes.Lab 2015; 95: 250-262Crossref podocytes endothelial AGEs bind receptor (RAGE), produce nucleotide-binding oligomerization domain–like pyrin domain containing 3 inflammasome.21Pichler Scholar,23Shahzad Bock Dong W. al.Nlrp3-inflammasome non-myeloid-derived aggravates nephropathy.Kidney 87: 74-84Abstract (234) Scholar,24Sakai N. Wada Revisiting nephropathy: Nlrp3 inflammasome resident cells.Kidney 12-14Abstract Together, κB induce interleukins (IL), IL-1β IL-18, respectively.24Sakai Moreover, serum A, RAGE activator, perpetuates feed-forward cycle gene 1).21Pichler signals lead ongoing mediators, factors, immune cell recruitment.19Zhao Scholar,21Pichler Notably, newer glucose-lowering agents, glucagon-like peptide-1 agonists (GLP-1 RAs), prevent CKD T2D, independent their effects.25Neuen B.L. Young Heerspink prevention patients diabetes: meta-analysis.Lancet Endocrinol. 7: 845-854Abstract (339) 26Cannon C.P. Perkovic Agarwal al.Evaluating canagliflozin events mellitus according baseline HbA1c, HbA1c <7%: CREDENCE trial.Circulation. 141: 407-410Crossref (65) 27Mann J.F.E. Buse J.B. Idorn al.Potential protection liraglutide semaglutide: Exploratory mediation analysis.Diabetes Obes Metab. 2021; 23: 2058-2066Crossref (3) 28Tuttle Lakshmanan Rayner B. al.Dulaglutide versus glargine moderate-to-severe (AWARD-7): multicentre, open-label, randomised trial.Lancet 2018; 6: 605-617Abstract (233) 29Kang Jardine M.J. offer benefit beyond diabetes.Nat 17: 83-84Crossref (12) By ameliorating glucotoxicity influx into potent anti-inflammatory effects. preclinical models suppresses hyperglycemia-induced species generation formation attenuates surrounding tubulointerstitial fibrosis.11Alicic Scholar,30Ojima Matsui Nishino al.Empagliflozin, exerts antifibrotic experimental nephropathy partly suppressing AGEs-receptor axis.Horm Metab Res. 47: 686-692Crossref Scholar,31Eleftheriadis Pissas G. Tsogka unifying model human effect dapagliflozin.Int Urol 52: 1179-1189Crossref GLP-1 RAs downregulate pathways nonpancreatic organs.32Alicic Cox Incretin drugs biological evidence.Nat 227-244Crossref (27) rodent RA decreased oxidative stress, transforming factor-beta (TGF-β1), intercellular adhesion molecule-1, tumor necrosis factor-α, IL-1β, macrophages kidney.32Alicic stress nicotinamide adenine dinucleotide phosphatase oxidase cyclic monophosphate–dependent heme oxygenase-1.33Kawanami D. Takashi outcomes mechanisms.Front Pharmacol. 11: 967Crossref (22) Scholar,34Yang H. Li Wang Z. al.Exendin-4 ameliorates ischemia-reperfusion injury rat.J Surg 182: 825-832Abstract (25) Inhibition signaling proposed suppression cytokine chemokine expression.32Alicic exposure occur diet hyperglycemia.20Reidy Scholar,35Uribarri J. Woodruff Goodman al.Advanced foods practical guide reduction diet.J Diet Assoc. 2010; 110: 911-916.e912Abstract (746) Dietary escape gastrointestinal absorption interact colonic microbiota,36Yacoub Nugent Cai restriction bacterial gut microbiota peritoneal dialysis patients; randomized open label controlled trial.PLoS One. 12e0184789Crossref (63) Scholar,37Snelson Coughlan products: digestion, modulation microbial ecology.Nutrients. 22: 215Crossref (82) triggering mediators.38Garay-Sevilla Beeri M.S. la Maza M.P. al.The endproducts development non-infectious diseases: narrative review.Nutr Res Rev. 33: 298-311Crossref (6) Activation RAGE-dependent causes mucosal barrier dysfunction translocation systemic circulation.39Raman K.G. Sappington P.L. Yang intestinal hemorrhagic shock.Am Gastrointest Liver 2006; 291: G556-G565Crossref Scholar,40Snelson Tan S.M. Clarke al.Processed permeability microvascular diseases.Sci Adv. 7eabe4841Crossref As progresses, greater amounts ammonia urea shift toward Gram-negative bacteria gut. Lipopolysaccharides walls toll-like receptor-4 production, recruitment lipopolysaccharides.41Zhang Meng microbiome mellitus.Diabetes Pract. 172: 108645Abstract Scholar,42Ramezani Raj D.S. microbiome, targeted interventions.J 25: 657-670Crossref (397) Exposure podocytes, these lipopolysaccharides injury, inflammation, fibrosis.43Ma Chadban S.J. Zhao C.Y. al.TLR4 promotes podocyte interstitial nephropathy.PLoS 9: e97985Crossref Diabetes-associated protective short-chain fatty disruption.41Zhang Scholar,44Mosterd Kanbay van den Born al.Intestinal derived metabolites inmodulation progression.Best Pract Endocrinol 35: 101484Crossref 45Reichardt Duncan S.H. al.Phylogenetic distribution three propionate microbiota.ISME 1323-1335Crossref (530) 46Diener Reyes-Escogido M.L. Jimenez-Ceja L.M. al.Progressive shifts reflect prediabetes treatment-naive Mexican cohort.Front (Lausanne). 602326Crossref (2) Complex especially essentially "diseases diseases," such present major challenges deciphering reproducible genetic contributions susceptibility severity.47Cole Florez J.C. Genetics complications.Nat 377-390Crossref (163) Advances acquiring large datasets genome-wide association yielded insights shed light predisposition DKD. Missense mutations COL4A3 gene, encodes structural component basement membrane (GBM), known Alport syndrome.48Salem R.M. Todd J.N. Sandholm al.Genome-wide study highlights biology involved collagen.J 30: 2000-2016Crossref Recently, variant (rs55703767) linked "diabetic nephropathy" T1D, suggesting disordered collagen expression.48Salem was most evident glycated hemoglobin. less GBM thickening glomerulosclerosis among either who biopsy data. Thus, "second-hit" phenomenon operative consequences hyperglycemia, damage. Variants genes (DDR1, COLEC11, BMP7) various phenotypes.48Salem contrast variants, APOL-l G1/G2 alleles observed African ancestry nondiabetic often when accompanied "second hit," viral illness interferon state.49Friedman D.J. Pollak M.R. APOL1 genetics applications.Clin 294-303Crossref (11) Another APOL-1 (rs9622363) recently reported meta-analysis American it progression.50Guan Keaton Dimitrov identifies novel loci diabetes-attributed end-stage Americans.Hum Genomics. 13: 21Crossref Among European cohort GABRR1 (rs9942471) highly microalbuminuria.51van Zuydam N.R. Ahlqvist E. subjects diab

Language: Английский

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Protection of mitochondria prevents high-fat diet–induced glomerulopathy and proximal tubular injury

Kidney International, Journal Year: 2016, Volume and Issue: 90(5), P. 997 - 1011

Published: Aug. 9, 2016

Obesity is a major risk factor for the development of chronic kidney disease, even independent its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding obesity-related disease glomerulopathy, glomerular hypertrophy, mesangial matrix expansion, focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition AMP kinase, endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure endothelial cells, podocytes, proximal tubular epithelial cells after 28 weeks high-fat diet C57BL/6 mice. Treatment SS-31, tetrapeptide that targets cardiolipin protects cristae structure, during preserved normal all restored kinase activity, prevented intracellular accumulation, stress, apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, loss glomerulosclerosis, macrophage infiltration, upregulation proinflammatory (TNF-α, MCP-1, NF-κB) profibrotic (TGF-β) cytokines. Thus, mitochondria protection can overcome lipotoxicity represent novel upstream target therapeutic development. independently dyslipidemia.1Wang Y. Chen X. Song et al.Association between obesity disease: systematic review meta-analysis.Kidney Int. 2008; 73: 19-33Abstract Full Text PDF PubMed Scopus (443) Google Scholar, 2Chertow G.M. Hsu C.Y. Johansen K.L. enlarging body evidence: disease.J Am Soc Nephrol. 2006; 17: 1501-1502Crossref (68) 3de Vries A.P. Ruggenenti P. Ruan X.Z. al.Fatty kidney: emerging role ectopic disease.Lancet Diabetes Endocrinol. 2014; 2: 417-426Abstract (268) Scholar glomerulosclerosis.3de 4Chen H.M. Liu Z.H. Zeng C.H. al.Podocyte lesions patients glomerulopathy.Am J Kidney Dis. 48: 772-779Abstract (149) Increasing evidence shows podocyte stress driving force proteinuria Patients glomerulopathy have reduced density, widened foot processes, proteinuria.4Chen Similar findings been reported mice just 2 4 months (HFD), before there any significant increase blood glucose.5Deji N. Kume S. Araki al.Structural functional kidneys diet-induced obese mice.Am Physiol Renal Physiol. 2009; 296: F118-F126Crossref (196) 6Shevalye H. Lupachyk Watcho al.Prediabetic nephropathy as an early consequence high-calorie/high-fat diet: relation oxidative stress.Endocrinology. 2012; 153: 1152-1161Crossref (35) 7Sun Y.B. Qu Howard V. al.Smad3 deficiency from obesity-induced injury precedes resistance.Kidney 2015; 88: 286-298Abstract (34) 8Ruggiero C. Ehrenshaft M. Cleland E. al.High-fat induces initial adaptation bioenergetics despite evident ROS production.Am Endocrinol Metab. 2011; 300: E1047-E1058Crossref (90) 9Wicks S.E. Nguyen T.T. Breaux al.Diet-induced - search susceptible mouse model.Biochimie. 2016; 124: 65-73Crossref (23) Another prominent feature accumulation vacuoles (PT) suggesting metabolism may be cause dysfunction.3de 10Herman-Edelstein Scherzer Tobar A. al.Altered human diabetic nephropathy.J Lipid Res. 55: 561-572Crossref (311) 11Martinez-Garcia Izquierdo-Lahuerta Vivas al.Renal lipotoxicity-associated inflammation affects actin cytoskeleton organization podocytes.PLoS One. 10: e0142291Google Intracellular causes (ER) cytoskeletal changes, activation processes.10Herman-Edelstein 12van der Heijden R.A. Bijzet J. Meijers W.C. al.Obesity-induced high fat challenged C57BL/6J associated acceleration age-dependent amyloidosis.Sci Rep. 5: 16474Crossref (52) Mitochondrial fatty acid β-oxidation source adenosine triphosphate (ATP) kidney. Excess acids are not oxidized by esterified glycerol deposited droplets. Gene analysis biopsy samples revealed pathways involved uptake decreased expression enzymes supporting β-oxidation.10Herman-Edelstein Mice fed HFD also showed downregulation key lipogenesis.13Kume Uzu T. al.Role altered induced diet.J 2007; 18: 2715-2723Crossref (189) Importantly, was correlation gene filtration rate nephropathy.10Herman-Edelstein (AMPK) plays metabolism. Activation AMPK reduces synthesis increases oxidation mitochondria. decreases activity multiple tissues, including kidney.13Kume 14Lindholm C.R. Ertel R.L. Bauwens J.D. al.A tissues absence hyperglycemia systemic rats.J Biochem. 2013; 69: 165-175Crossref (97) 15Decleves A.E. Mathew A.V. Cunard R. al.AMPK mediates initiation 22: 1846-1855Crossref (176) activator (5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside) tubulointerstitial fibrosis.15Decleves 16Decleves Zolkipli Z. Satriano al.Regulation AMP-activated injury.Kidney 85: 611-623Abstract (158) Chronic 5-aminoimidazole-4-carboxamide-1-β-d-ribonucleoside treatment cells.16Decleves There suggest inhibit numerous reports structures obesity. PT ob/ob small rounded membranes density.17Stacchiotti Favero G. Giugno L. al.Mitochondrial metabolic dysfunction convoluted tubules mice: protective melatonin.PLoS 9: e111141Crossref (46) fragmentation, ATP content, increased H2O2 emission HFD, mice, rat model type 1 diabetes.8Ruggiero 18Munusamy do Carmo J.M. Hosler J.P. presence leptin.Am 309: F731-F743Crossref (20) 19Coughlan M.T. T.V. Penfold S.A. al.Mapping time-course adaptations experimental diabetes.Clin Sci (Lond). 130: 711-720Crossref (83) structural indicative damage Protection (d-Arg-2′,6′-dimethylTyr-Lys-Phe-NH2), peptide structure,20Birk Soong al.The mitochondrial-targeted compound re-energizes ischemic interacting cardiolipin.J 24: 1250-1261Crossref (297) 21Birk Chao W.M. Bracken al.Targeting cytochrome c/cardiolipin complex promote electron transport optimize synthesis.Br Pharmacol. 171: 2017-2028Crossref (190) 22Szeto H.H. Birk Serendipity discovery compounds restore plasticity.Clin Pharmacol Ther. 96: 672-683Crossref (116) ER HFD. Interestingly, resistance, These support mitochondrion therapeutics. were maintained (ND) weeks. This specific has weight, fat, glucose, insulin, 16 mice.23Kang Dai Lustig M.E. al.Heterozygous SOD2 deletion impairs glucose-stimulated secretion, but action, high-fat-fed mice.Diabetes. 63: 3699-3710Crossref (36) received 5-day regimen low-dose streptozotocin (STZ) start minimize hyperinsulinemia. then treated either saline solution daily (1 mg/kg s.c.) 8 only slightly relative ND, dramatically (Figure 1a). Nonfasting glucose 1b), indicating dose STZ did pancreatic β cells. Oral tolerance tests administered clearance 1c d), onset Plasma significantly elevated HFD.13Kume clearance, 1a–d). Pathology stages humans primarily related changes.24Thakur Morse Reisin Functional obesity.Contrib 151: 135-150Crossref (11) Periodic acid–Schiff staining capillary collapse expansion 2a). Preliminary studies alone, caused these (Supplementary Figure S1). Collagen IV deposition detected immunohistochemical 2b). Trichrome glomerulosclerosis 2c). Mesangial confirmed transmission microscopy (TEM) 2d). change size 2e), periodic acid–Schiff–positive collagen 2f g). Transforming growth factor-β fibrosis, TGF-β cortical tissue 2h). completely 2a–h) having 1).Figure 2SS-31 prevents glomeruli (HFD). (a) Representative images (PAS) stain (ND), HFD+SS-31 (b) immunostaining (c) trichrome (d) microscopic showing podocytes (P), (E), loops (CL), mesangium (M). (e) Glomerular (f,g) Densitometric analyses PAS show (4 each group). (h) Western blot densitometric transforming (TGF-β [4 group]). All data shown mean ± SEM. Statistical performed 1-way variance followed Tukey's comparisons test. *P < 0.05, **P 0.01, ***P 0.001.View Large Image ViewerDownload (PPT) TEM indicated compression capillaries A decrease CD31, marker, 3a). CD31 3b). In addition led injury, von Willebrand (vWF) vWF glycoprotein platelet adhesion subendothelium at sites vascular normally expressed glomeruli.25Pusztaszeri M.P. Seelentag W. Bosman F.T. Immunohistochemical markers CD34, factor, Fli-1 tissues.J Histochem Cytochem. 54: 385-395Crossref (585) barely ND 10-fold 3c). Vascular constitutively upregulated animals diabetes.26Schrijvers B.F. Flyvbjerg De Vriese A.S. (VEGF) pathophysiology.Kidney 2004; 65: 2003-2017Abstract (400) almost 4-fold 3d). Obesity-related density foot-process width.4Chen 5Deji Wilms tumor cyclin-dependent inhibitor p57 widely used within glomerulus.27Pichaiwong Hudkins Wietecha al.Reversibility advanced 1088-1102Crossref (130) Podocyte number, determined nuclear 1, abolished 4a b ). reduction 1–positive nuclei corresponded 4c). surviving irregular shapes flattened processes some areas effacement, which 4d). feeding known infiltration plasma necrosis factor-α (TNF-α) monocyte chemoattractant protein (MCP-1).12van We found number CD68+ macrophages per glomerulus 5a tissue, MCP-1 5c) TNF-α 5d). factor-κB regulator inflammatory response, p65–nuclear 5e). 50% 5b) 5c–e). Tubular occurs later than nephropathy.28Reidy K. Kang Hostetter al.Molecular Clin Invest. 2333-2340Crossref (505) After outer medulla relatively brush border 6a). Closer examination, however, vacuolization most 6b). Such previously described droplets 14 HFD.29Mount Davies Choy S.W. al.Obesity-related disease-the metabolism.Metabolites. 720-732Crossref (45) further examined 6c–j). many elongated 6c). Although appears fill cytoplasm 6d–h). Some very large 6d), microscopic, without limiting membrane 6e–h). surrounded crescent-shaped, double-walled membranes, consistent macrolipophagy 6f–h).30Dong Czaja M.J. Regulation autophagy.Trends 234-240Abstract (156) Others autophagosomes containing lipids 6g) myelin figures 6h). peripheral chromatin condensation seen 6d suggestive apoptotic autophagic 6i j). Terminal deoxynucleotidyltransferase–mediated dUTP nick end-labeling (TUNEL) quantitatively assess incidence apoptosis TUNEL-positive rarely 7a). tuft 7c) parietal 7d). 7e). cell types 7a–e). Despite apoptosis, peritubular interstitial fibrosis S2). pathway other tissues.13Kume 31Long Y.C. Zierath J.R. signaling regulation.J 116: 1776-1783Crossref (764) As previously,14Lindholm phospho-AMPK/AMPK ratio this ameliorated 8a). contrast, Akt (phospho-Akt/Akt ratio) 8b), sensitivity treatment. Decreased content reflect HFD.32Reznick R.M. Shulman G.I. biogenesis.J 574: 33-39Crossref (291) contain densely stacked organized along compartments 9a disorganized 9c d). Cristae few replaced homogenized 9e f). appear inner often rupture 9g). Conversely, 9h i). contains abundant rough 10a–c typically double dense matrix, though individual difficult visualize 10c). Podocytes fewer organelles 10e). round distended 10f). addition, small, 10g). cellular 10i j), 10k). Few 10d). they identified their structure. Endothelial intact lost 10h). appearance, 10-l). Human cells.3de exact mechanism produces fully understood. Our results excess lead types, size, density. Because complexes chain located contributes prod

Language: Английский

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