scholarly journals Prompt apoptotic response to high glucose in SGLT-expressing renal cells

2019 ◽  
Vol 316 (5) ◽  
pp. F1078-F1089 ◽  
Author(s):  
Linnéa M. Nilsson ◽  
Liang Zhang ◽  
Alexander Bondar ◽  
Daniel Svensson ◽  
Annika Wernerson ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
High Glucose ◽  
Glucose Transporter ◽  
Mesangial Cells ◽  
Cell Types ◽  
Moderate Increase ◽  
Renal Cells ◽  
Apoptotic Response ◽  
Proximal Tubule Cells ◽  
Tubule Cells

It is generally believed that cells that are unable to downregulate glucose transport are particularly vulnerable to hyperglycemia. Yet, little is known about the relation between expression of glucose transporters and acute toxic effects of high glucose exposure. In the present ex vivo study of rat renal cells, we compared the apoptotic response to a moderate increase in glucose concentration. We studied cell types that commonly are targeted in diabetic kidney disease (DKD): proximal tubule cells, which express Na+-dependent glucose transporter (SGLT)2, mesangial cells, which express SGLT1, and podocytes, which lack SGLT and take up glucose via insulin-dependent glucose transporter 4. Proximal tubule cells and mesangial cells responded within 4–8 h of exposure to 15 mM glucose with translocation of the apoptotic protein Bax to mitochondria and an increased apoptotic index. SGLT downregulation and exposure to SGLT inhibitors abolished the apoptotic response. The onset of overt DKD generally coincides with the onset of albuminuria. Albumin had an additive effect on the apoptotic response. Ouabain, which interferes with the apoptotic onset, rescued from the apoptotic response. Insulin-supplemented podocytes remained resistant to 15 and 30 mM glucose for at least 24 h. Our study points to a previously unappreciated role of SGLT-dependent glucose uptake as a risk factor for diabetic complications and highlights the importance of therapeutic approaches that specifically target the different cell types in DKD.

scholarly journals Single-cell Analysis of ACE2 Expression in Human Kidneys and Bladders Reveals a Potential Route of 2019-nCoV Infection

2020 ◽  
Author(s):  
Wei Lin ◽  
Longfei Hu ◽  
Yan Zhang ◽  
Joshua D. Ooi ◽  
Ting Meng ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Kidney Injury ◽  
Cell Types ◽  
Gene Expressions ◽  
Proximal Tubule Cells ◽  
Bladder Cell ◽  
Short Period ◽  
Tubule Cells

AbstractSince December 2019, a novel coronavirus named 2019 coronavirus (2019-nCoV) has emerged in Wuhan of China and spread to several countries worldwide within just one month. Apart from fever and respiratory complications, acute kidney injury has been observed in some patients with 2019-nCoV. In a short period of time, angiotensin converting enzyme II (ACE2), have been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same for severe acute respiratory syndrome coronavirus (SARS). To investigate the possible cause of kidney damage in 2019-nCoV patients, we used both published kidney and bladder cell atlas data and an independent unpublished kidney single cell RNA-Seq data generated in-house to evaluate ACE2 gene expressions in all cell types in healthy kidneys and bladders.Our results showed the enriched expression of all subtypes of proximal tubule cells of kidney and low but detectable levels of expression in bladder epithelial cells. These results indicated the urinary system is a potential route for 2019-nCoV infection, along with the respiratory system and digestion system. Our findings suggested the kidney abnormalities of SARS and 2019-nCoV patients may be due to proximal tubule cells damage and subsequent systematic inflammatory response induced kidney injury. Beyond that, laboratory tests of viruses and related indicators in urine may be needed in some special patients of 2019-nCoV.

Role of cytochrome P-450 epoxygenase metabolites in EGF signaling in renal proximal tubule

1995 ◽  
Vol 269 (4) ◽  
pp. C831-C840 ◽  
Author(s):  
K. D. Burns ◽  
J. Capdevila ◽  
S. Wei ◽  
M. D. Breyer ◽  
T. Homma ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Thymidine Incorporation ◽  
Primary Cultures ◽  
Cell Types ◽  
Renal Proximal Tubule ◽  
Epoxyeicosatrienoic Acid ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Cell Mitogen ◽  
Cytochrome P 450

Epidermal growth factor (EGF) is a potent epithelial cell mitogen and induces eicosanoid production in many cell types. The present study examined signaling mechanisms for EGF in the renal proximal tubule, where high concentrations of cytochrome P-450 epoxygenase have been reported. In primary cultures of rabbit proximal tubule cells, EGF (30 nM) increased endogenous epoxyeicosatrienoic acid (EET) levels 5.3 +/- 1.4-fold within 10 min (n = 6). In these cells EGF-stimulated [3H]thymidine incorporation was significantly inhibited by the cytochrome P-450 inhibitors ketoconazole or clotrimazole but not by the cyclooxygenase inhibitor indomethacin. In fura 2-loaded proximal tubule cells, EGF caused a concentration-dependent increase in cytosolic Ca2+ concentration ([Ca2+]i), due to Ca2+ influx, which was inhibited by either ketoconazole or SKF-525A but not by indomethacin. Addition of 5,6-EET (0.5 microM) also induced Ca2+ influx in proximal tubule cells, whereas 8,9-11,12-, or 14,15-EET did not. In cells treated with bis(2-amino-5-methylphenoxy)ethane N,N,N',N'-tetraacetic acid tetraacetoxy-methyl ester to chelate [Ca2+]i, EGF-stimulated [3H]thymidine incorporation. These results indicate that EGF increases EET levels in proximal tubule and suggest that 5,6-EET or its metabolites may be a modulator of EGF-induced [Ca2+]i increases and involved in mitogenesis.

scholarly journals Mechanism of increased clearance of glycated albumin by proximal tubule cells

2016 ◽  
Vol 310 (10) ◽  
pp. F1089-F1102 ◽  
Author(s):  
Mark C. Wagner ◽  
Jered Myslinski ◽  
Shiv Pratap ◽  
Brittany Flores ◽  
George Rhodes ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Structural Changes ◽  
Dissociation Constants ◽  
Glycated Albumin ◽  
Cell Types ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Equilibrium Dissociation Constants ◽  
Equilibrium Dissociation ◽  
The Impact

Serum albumin is the most abundant plasma protein and has a long half-life due to neonatal Fc receptor (FcRn)-mediated transcytosis by many cell types, including proximal tubule cells of the kidney. Albumin also interacts with, and is modified by, many small and large molecules. Therefore, the focus of the present study was to address the impact of specific known biological albumin modifications on albumin-FcRn binding and cellular handling. Binding at pH 6.0 and 7.4 was performed since FcRn binds albumin strongly at acidic pH and releases it after transcytosis at physiological pH. Equilibrium dissociation constants were measured using microscale thermophoresis. Since studies have shown that glycated albumin is excreted in the urine at a higher rate than unmodified albumin, we studied glucose and methylgloxal modified albumins (21 days). All had reduced affinity to FcRn at pH 6.0, suggesting these albumins would not be returned to the circulation via the transcytotic pathway. To address why modified albumin has reduced affinity, we analyzed the structure of the modified albumins using small-angle X-ray scattering. This analysis showed significant structural changes occurring to albumin with glycation, particularly in the FcRn-binding region, which could explain the reduced affinity to FcRn. These results offer an explanation for enhanced proximal tubule-mediated sorting and clearance of abnormal albumins.

scholarly journals PROTEIN TRANSPORT IN MOUSE KIDNEY UTILIZING TYROSINASE AS AN ULTRASTRUCTURAL TRACER

1972 ◽  
Vol 136 (2) ◽  
pp. 291-304 ◽  
Author(s):  
Constance Oliver ◽  
Edward Essner
Keyword(s):  
Basement Membrane ◽  
Proximal Tubule ◽  
Protein Transport ◽  
Mesangial Cells ◽  
Mouse Kidney ◽  
Border Region ◽  
Cell Coat ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Additional Support

The morphological basis of glomerular filtration and protein reabsorption in mouse kidney was examined by using mushroom tyrosinase subunits (mol wt 34,500), as an ultrastructural tracer. Almost immediately after injection tyrosinase reaction product was visualized in the glomerulus, and within the capillary lumen extending into the endothelial fenestrae. The entire basement membrane showed accumulations of tyrosinase in the subendothelial and subepithelial layers. The urinary space contained considerable amounts of reaction product, some of which was adsorbed to the cell coat of the podocytes. Reaction product could also be seen in the brush border region of the proximal tubule cells. By 30 min after injection, no tyrosinase reaction product was demonstrable in the glomerulus except for dense vesicles in mesangial cells. Most of the reaction product was localized in absorption droplets in the apical cytoplasm of proximal tubule cells. Occasionally, some tyrosinase reaction product was present within the basal infoldings of these cells. The behavior of tyrosinase in the mouse kidney is in accordance with that of other low molecular weight tracers. The pattern of localization within the basement membrane provides additional support for the presence of two filtration barriers in the glomerulus. The adherence of tyrosinase to the cell coat of the glomerular epithelial cells suggests that this may be an additional mechanism whereby protein is removed from the glomerular filtrate. Tyrosinase subunits may prove to be a useful new tracer for the study of protein transport.

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