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Imaging mass spectrometry reveals direct albumin fragmentation within the diabetic kidney.
Grove KJ, Lareau NM, Voziyan PA, Zeng F, Harris RC, Hudson BG, Caprioli RM
(2018) Kidney Int 94: 292-302
MeSH Terms: Albumins, Albuminuria, Animals, Cathepsin D, Diabetic Nephropathies, Disease Models, Animal, Frozen Sections, Humans, Kidney Glomerulus, Kidney Tubules, Mice, Mice, Inbred C57BL, Molecular Imaging, Nitric Oxide Synthase Type III, Proteolysis, Renal Elimination, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 29, 2018
Albumin degradation in the renal tubules is impaired in diabetic nephropathy such that levels of the resulting albumin fragments increase with the degree of renal injury. However, the mechanism of albumin degradation is unknown. In particular, fragmentation of the endogenous native albumin has not been demonstrated in the kidney and the enzymes that may contribute to fragmentation have not been identified. To explore this we utilized matrix-assisted laser desorption/ionization imaging mass spectrometry for molecular profiling of specific renal regions without disturbing distinct tissue morphology. Changes in protein expression were measured in kidney sections of eNOSdb/db mice, a model of diabetic nephropathy, by high spatial resolution imaging allowing molecular localizations at the level of single glomeruli and tubules. Significant increases were found in the relative abundances of several albumin fragments in the kidney of the mice with diabetic nephropathy compared with control nondiabetic mice. The relative abundance of fragments detected correlated positively with the degree of nephropathy. Furthermore, specific albumin fragments accumulating in the lumen of diabetic renal tubules were identified and predicted the enzymatic action of cathepsin D based on cleavage specificity and in vitro digestions. Importantly, this was demonstrated directly in the renal tissue with the endogenous nonlabeled murine albumin. Thus, our results provide molecular insights into the mechanism of albumin degradation in diabetic nephropathy.
Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
1 Communities
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17 MeSH Terms
Gene-Edited Human Kidney Organoids Reveal Mechanisms of Disease in Podocyte Development.
Kim YK, Refaeli I, Brooks CR, Jing P, Gulieva RE, Hughes MR, Cruz NM, Liu Y, Churchill AJ, Wang Y, Fu H, Pippin JW, Lin LY, Shankland SJ, Vogl AW, McNagny KM, Freedman BS
(2017) Stem Cells 35: 2366-2378
MeSH Terms: Animals, Cell Adhesion, Cell Differentiation, Gene Editing, Humans, Kidney, Kidney Glomerulus, Mice, Organoids, Pluripotent Stem Cells, Podocytes, Sialoglycoproteins
Show Abstract · Added March 14, 2019
A critical event during kidney organogenesis is the differentiation of podocytes, specialized epithelial cells that filter blood plasma to form urine. Podocytes derived from human pluripotent stem cells (hPSC-podocytes) have recently been generated in nephron-like kidney organoids, but the developmental stage of these cells and their capacity to reveal disease mechanisms remains unclear. Here, we show that hPSC-podocytes phenocopy mammalian podocytes at the capillary loop stage (CLS), recapitulating key features of ultrastructure, gene expression, and mutant phenotype. hPSC-podocytes in vitro progressively establish junction-rich basal membranes (nephrin podocin ZO-1 ) and microvillus-rich apical membranes (podocalyxin ), similar to CLS podocytes in vivo. Ultrastructural, biophysical, and transcriptomic analysis of podocalyxin-knockout hPSCs and derived podocytes, generated using CRISPR/Cas9, reveals defects in the assembly of microvilli and lateral spaces between developing podocytes, resulting in failed junctional migration. These defects are phenocopied in CLS glomeruli of podocalyxin-deficient mice, which cannot produce urine, thereby demonstrating that podocalyxin has a conserved and essential role in mammalian podocyte maturation. Defining the maturity of hPSC-podocytes and their capacity to reveal and recapitulate pathophysiological mechanisms establishes a powerful framework for studying human kidney disease and regeneration. Stem Cells 2017;35:2366-2378.
© 2017 AlphaMed Press.
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MeSH Terms
Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis.
Borza CM, Su Y, Tran TL, Yu L, Steyns N, Temple KJ, Skwark MJ, Meiler J, Lindsley CW, Hicks BR, Leitinger B, Zent R, Pozzi A
(2017) Matrix Biol 57-58: 258-271
MeSH Terms: Acute Kidney Injury, Angiotensins, Animals, Binding Sites, Collagen Type IV, Discoidin Domain Receptor 1, Epithelial Cells, Gene Expression Regulation, Humans, Kidney Glomerulus, Male, Mice, Mice, Knockout, Nephrectomy, Nephritis, Protein Binding, Signal Transduction, Ureter, Ureteral Obstruction
Show Abstract · Added March 26, 2017
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagens. DDR1 expression increases following kidney injury and accumulating evidence suggests that it contributes to the progression of injury. To this end, deletion of DDR1 is beneficial in ameliorating kidney injury induced by angiotensin infusion, unilateral ureteral obstruction, or nephrotoxic nephritis. Most of the beneficial effects observed in the DDR1-null mice are attributed to reduced inflammatory cell infiltration to the site of injury, suggesting that DDR1 plays a pro-inflammatory effect. The goal of this study was to determine whether, in addition to its pro-inflammatory effect, DDR1 plays a deleterious effect in kidney injury by directly regulating extracellular matrix production. We show that DDR1-null mice have reduced deposition of glomerular collagens I and IV as well as decreased proteinuria following the partial renal ablation model of kidney injury. Using mesangial cells isolated from DDR1-null mice, we show that these cells produce significantly less collagen compared to DDR1-null cells reconstituted with wild type DDR1. Moreover, mutagenesis analysis revealed that mutations in the collagen binding site or in the kinase domain significantly reduce DDR1-mediated collagen production. Finally, we provide evidence that blocking DDR1 kinase activity with an ATP-competitive small molecule inhibitor reduces collagen production. In conclusion, our studies indicate that the kinase activity of DDR1 plays a key role in DDR1-induced collagen synthesis and suggest that blocking collagen-mediated DDR1 activation may be beneficial in fibrotic diseases.
Copyright © 2016. Published by Elsevier B.V.
1 Communities
2 Members
1 Resources
19 MeSH Terms
Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury.
Laskowski J, Renner B, Le Quintrec M, Panzer S, Hannan JP, Ljubanovic D, Ruseva MM, Borza DB, Antonioli AH, Pickering MC, Holers VM, Thurman JM
(2016) Kidney Int 90: 109-22
MeSH Terms: Animals, Complement C3, Complement Factor H, Complement Pathway, Alternative, Glomerulonephritis, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Receptors, Complement
Show Abstract · Added December 2, 2016
Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Antibodies to α5 chain of collagen IV are pathogenic in Goodpasture's disease.
Cui Z, Zhao MH, Jia XY, Wang M, Hu SY, Wang SX, Yu F, Brown KL, Hudson BG, Pedchenko V
(2016) J Autoimmun 70: 1-11
MeSH Terms: Aged, Amino Acid Sequence, Animals, Anti-Glomerular Basement Membrane Disease, Autoantibodies, Autoantigens, Autoimmunity, Biopsy, Case-Control Studies, Cell Line, Tumor, Collagen Type IV, Disease Models, Animal, Epitope Mapping, Epitopes, Female, Humans, Kidney Glomerulus, Male, Models, Molecular, Protein Conformation, Protein Subunits, Rats, Rats, Inbred WKY
Show Abstract · Added June 14, 2016
Autoantibody against glomerular basement membrane (GBM) plays a direct role in the initiation and development of Goodpasture's (GP) disease. The principal autoantigen is the non-collagenous domain 1 (NC1) of α3 chain of collagen IV, with two immunodominant epitopes, EA-α3 and EB-α3. We recently demonstrated that antibodies targeting α5NC1 are bound to kidneys in GP patients, suggesting their pathogenic relevance. In the present study, we sought to assess the pathogenicity of the α5 autoantibody with clinical and animal studies. Herein, we present a special case of GP disease with circulating autoantibody reactive exclusively to the α5NC1 domain. This autoantibody reacted with conformational epitopes within GBM collagen IV hexamer and produced a linear IgG staining on frozen sections of human kidney. The antibody binds to the two regions within α5NC1 domain, EA and EB, and inhibition ELISA indicates that they are targeted by distinct sub-populations of autoantibodies. Sequence analysis highlights five residues that determine specificity of antibody targeting EA and EB epitopes of α5NC1 over homologous regions in α3NC1. Furthermore, immunization with recombinant α5NC1 domain induced crescentic glomerulonephritis and alveolar hemorrhage in Wistar-Kyoto rats. Thus, patient data and animal studies together reveal the pathogenicity of α5 antibodies. Given previously documented cases of GP disease with antibodies selectively targeting α3NC1 domain, our data presents a conundrum of why α3-specific antibodies developing in majority of GP patients, with α5-specific antibodies emerged in isolated cases, the answer for which is critical for understanding of etiology and progression of the GP disease.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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1 Members
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23 MeSH Terms
Novel methods for microCT-based analyses of vasculature in the renal cortex reveal a loss of perfusable arterioles and glomeruli in eNOS-/- mice.
Perrien DS, Saleh MA, Takahashi K, Madhur MS, Harrison DG, Harris RC, Takahashi T
(2016) BMC Nephrol 17: 24
MeSH Terms: Animals, Arterioles, Kidney Cortex, Kidney Glomerulus, Male, Mice, Mice, Knockout, Nitric Oxide Synthase Type III, Organ Size, Renal Artery, X-Ray Microtomography
Show Abstract · Added April 13, 2017
BACKGROUND - Two-dimensional measures of vascular architecture provide incomplete information about vascular structure. This study applied a novel rigorous method for 3D microCT-based analysis of total and cortical renal vasculature combined with a novel method to isolate and quantify the number of perfused glomeruli to assess vascular changes in eNOS-/- mice.
METHODS - Two month old male wildtype and eNOS-/- mice were perfused with heparinized saline followed by radiopaque Microfil. The Microfil-perfused vasculature of excised kidneys was imaged by μCT with an isotropic voxel-size of 5.0 μm. For analysis of renal cortical vasculature, a custom algorithm was created to define the cortical volume of interest (VOI) as the entire volume within 600 μm of the renal surface. Vessel thickness in the whole kidney or renal cortex was analyzed by plotting the distribution of vascular volume at each measured thickness and examining differences between the genotypes at individual thicknesses. A second image processing algorithm was created to isolate, identify, and extract contrast perfused glomeruli from the cortical vessels.
RESULTS - Fractional vascular volume (vascular volume/kidney volume; VV/KV) and Vessel Number/mm (V.N) were significantly lower in eNOS-/- mice vs. WT (p < 0.05). eNOS-/- kidneys had significantly fewer perfusable vessels vs. WT in the range of 20-40 μm in thickness. The cortex of eNOS-/- kidneys had significantly lower VV, VV/cortical volume, and V.N, with an increase in the distance between vessels (all p < 0.05). The total volume of vessels in the range of 20-30 μm was significantly lower in the cortex of eNOS-/- mice compared to WT (p < 0.05). Moreover, the total number of perfused glomeruli was significantly decreased in eNOS-/- mice (p < 0.01).
CONCLUSIONS - The methods presented here demonstrate a new method to analyze contrast enhanced μCT images for vascular phenotyping of the murine kidney. These data also demonstrate that kidneys in eNOS-/- mice have severe defects in vascular perfusion/structure in the renal cortex.
2 Communities
3 Members
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11 MeSH Terms
Integrated compensatory network is activated in the absence of NCC phosphorylation.
Grimm PR, Lazo-Fernandez Y, Delpire E, Wall SM, Dorsey SG, Weinman EJ, Coleman R, Wade JB, Welling PA
(2015) J Clin Invest 125: 2136-50
MeSH Terms: Amiloride, Ammonia, Animals, Biological Transport, Blood Pressure, Carbonic Anhydrases, Chlorides, Disease Models, Animal, Enzyme Activation, Epithelial Sodium Channels, Gene Expression Profiling, Gene Regulatory Networks, Gitelman Syndrome, Ketoglutaric Acids, Kidney Glomerulus, Male, Mice, Mice, Knockout, Natriuresis, Nephrons, Paracrine Communication, Phosphorylation, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Receptors, Notch, Receptors, Purinergic P2, Renal Reabsorption, Signal Transduction, Sodium Chloride, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 3
Show Abstract · Added May 3, 2017
Thiazide diuretics are used to treat hypertension; however, compensatory processes in the kidney can limit antihypertensive responses to this class of drugs. Here, we evaluated compensatory pathways in SPAK kinase-deficient mice, which are unable to activate the thiazide-sensitive sodium chloride cotransporter NCC (encoded by Slc12a3). Global transcriptional profiling, combined with biochemical, cell biological, and physiological phenotyping, identified the gene expression signature of the response and revealed how it establishes an adaptive physiology. Salt reabsorption pathways were created by the coordinate induction of a multigene transport system, involving solute carriers (encoded by Slc26a4, Slc4a8, and Slc4a9), carbonic anhydrase isoforms, and V-type H⁺-ATPase subunits in pendrin-positive intercalated cells (PP-ICs) and ENaC subunits in principal cells (PCs). A distal nephron remodeling process and induction of jagged 1/NOTCH signaling, which expands the cortical connecting tubule with PCs and replaces acid-secreting α-ICs with PP-ICs, were partly responsible for the compensation. Salt reabsorption was also activated by induction of an α-ketoglutarate (α-KG) paracrine signaling system. Coordinate regulation of a multigene α-KG synthesis and transport pathway resulted in α-KG secretion into pro-urine, as the α-KG-activated GPCR (Oxgr1) increased on the PP-IC apical surface, allowing paracrine delivery of α-KG to stimulate salt transport. Identification of the integrated compensatory NaCl reabsorption mechanisms provides insight into thiazide diuretic efficacy.
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31 MeSH Terms
Shear stress is normalized in glomerular capillaries following ⅚ nephrectomy.
Ferrell N, Sandoval RM, Bian A, Campos-Bilderback SB, Molitoris BA, Fissell WH
(2015) Am J Physiol Renal Physiol 308: F588-93
MeSH Terms: Animals, Blood Pressure, Capillaries, Hematocrit, Hemorheology, Kidney Glomerulus, Male, Nephrectomy, Rats, Wistar, Renal Circulation, Renal Insufficiency, Stress, Mechanical
Show Abstract · Added February 22, 2016
Loss of significant functional renal mass results in compensatory structural and hemodynamic adaptations in the nephron. While these changes have been characterized in several injury models, how they affect hemodynamic forces at the glomerular capillary wall has not been adequately characterized, despite their potential physiological significance. Therefore, we used intravital multiphoton microscopy to measure the velocity of red blood cells in individual glomerular capillaries of normal rats and rats subjected to ⅚ nephrectomy. Glomerular capillary blood flow rate and wall shear stress were then estimated using previously established experimental and mathematical models to account for changes in hematocrit and blood rheology in small vessels. We found little change in the hemodynamic parameters in glomerular capillaries immediately following injury. At 2 wk postnephrectomy, significant changes in individual capillary blood flow velocity and volume flow rate were present. Despite these changes, estimated capillary wall shear stress was unchanged. This was a result of an increase in capillary diameter and changes in capillary blood rheology in nephrectomized rats.
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12 MeSH Terms
Diabetic nephropathy induces alterations in the glomerular and tubule lipid profiles.
Grove KJ, Voziyan PA, Spraggins JM, Wang S, Paueksakon P, Harris RC, Hudson BG, Caprioli RM
(2014) J Lipid Res 55: 1375-85
MeSH Terms: Animals, Diabetic Nephropathies, Glycolipids, Kidney Glomerulus, Kidney Tubules, Mice, Mice, Knockout, Phospholipids
Show Abstract · Added October 27, 2014
Diabetic nephropathy (DN) is a major life-threatening complication of diabetes. Renal lesions affect glomeruli and tubules, but the pathogenesis is not completely understood. Phospholipids and glycolipids are molecules that carry out multiple cell functions in health and disease, and their role in DN pathogenesis is unknown. We employed high spatial resolution MALDI imaging MS to determine lipid changes in kidneys of eNOS(-/-) db/db mice, a robust model of DN. Phospholipid and glycolipid structures, localization patterns, and relative tissue levels were determined in individual renal glomeruli and tubules without disturbing tissue morphology. A significant increase in the levels of specific glomerular and tubular lipid species from four different classes, i.e., gangliosides, sulfoglycosphingolipids, lysophospholipids, and phosphatidylethanolamines, was detected in diabetic kidneys compared with nondiabetic controls. Inhibition of nonenzymatic oxidative and glycoxidative pathways attenuated the increase in lipid levels and ameliorated renal pathology, even though blood glucose levels remained unchanged. Our data demonstrate that the levels of specific phospho- and glycolipids in glomeruli and/or tubules are associated with diabetic renal pathology. We suggest that hyperglycemia-induced DN pathogenic mechanisms require intermediate oxidative steps that involve specific phospholipid and glycolipid species.
Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.
2 Communities
5 Members
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8 MeSH Terms
Glomerular cell cross-talk influences composition and assembly of extracellular matrix.
Byron A, Randles MJ, Humphries JD, Mironov A, Hamidi H, Harris S, Mathieson PW, Saleem MA, Satchell SC, Zent R, Humphries MJ, Lennon R
(2014) J Am Soc Nephrol 25: 953-66
MeSH Terms: Cells, Cultured, Coculture Techniques, Culture Media, Conditioned, Extracellular Matrix, Extracellular Matrix Proteins, Humans, Kidney Glomerulus, Phenotype, Podocytes, Protein Interaction Maps, Receptor Cross-Talk
Show Abstract · Added February 25, 2014
The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus that contains tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore, functionally linked to glomerular filtration. Although the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM are not well understood. To characterize specific cellular contributions to the GBM, we used mass spectrometry-based proteomics to analyze ECM isolated from podocytes and glomerular endothelial cells in vitro. These analyses identified cell type-specific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared with monoculture ECMs, and electron microscopy revealed basement membrane-like ECM deposition between cocultured cells, suggesting the involvement of cell-cell cross-talk in the production of glomerular ECM. Notably, compared with monoculture ECM proteomes, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings show the complexity of the glomerular ECM and suggest that both ECM composition and organization are context-dependent.
Copyright © 2014 by the American Society of Nephrology.
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11 MeSH Terms