Altered renal proximal tubule cell ion homeostasis during diabetes

1993 ◽  
Vol 51 ◽  
pp. 12-13
Author(s):  
Craig C. Freudenrich ◽  
Daniel Hockett ◽  
Benjamin Kirk ◽  
Kurt Gilliland ◽  
Brian Scherer ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Ion Homeostasis ◽  
Diabetic Rats ◽  
Proximal Tubule Cell ◽  
Sprague Dawley ◽  
Tubule Cell ◽  
Electrolyte Excretion ◽  
Proximal Tubule Cells ◽  
Sprague Dawley Rats ◽  
Renal Tubule Cell

A major characteristic of human and experimental diabetes mellitus is enhanced urinary excretion of electrolytes (e.g. Na, K, Mg, Ca). The increased urinary electrolyte excretion can lead to low serum electrolyte concentrations (e.g. hypomagnesemia, hyponatremia, hypocalcemia, hypokalemia), although this issue remains controversial. Ultimately, elevated urinary electrolyte excretion can result in mineral deficiencies which have important consequences such as retinopathies, convulsions, osteoporosis, arrhythmias, and sudden death ischemia. The increased urinary electrolyte excretion could be due to osmotic diuresis and/or altered renal tubule cell ion homeostasis; however, few studies have addressed whether diabetes alters specific tubule cell ion homeostasis. In this study, we used electron probe x-ray microanalysis (EPXMA) to obtain quantitative microchemical images of proximal tubule cells from diabetic rats so that we could define how subcellular ion homeostasis is altered during diabetes.Adult male Sprague-Dawley rats were housed in individual metabolic cages and urine output was measured daily; peri-orbital plasma samples were collected every 3 days. Urine and plasma ion concentrations (Na, K, Ca, Mg) were assayed by atomic absorption spectroscopy, blood glucose was measured with a commercial glucometer, and urine glucose and ketones were detected with commercial strips.

Parathyroid hormone (PTH) decreases sodium-phosphate cotransporter type IIa (NpT2a) mRNA stability

2013 ◽  
Vol 304 (8) ◽  
pp. F1076-F1085 ◽  
Author(s):  
Rebecca D. Murray ◽  
Kristine Holthouser ◽  
Barbara J. Clark ◽  
Sarah A. Salyer ◽  
Michelle T. Barati ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Proximal Tubule Cells ◽  
Opossum Kidney ◽  
Salt Wasting ◽  
Sprague Dawley Rats ◽  
Culture Models

The acute inhibitory effects of parathyroid hormone (PTH) on proximal tubule Na+-K+-ATPase (Na-K) and sodium-dependent phosphate (NaPi) transport have been extensively studied, while little is known about the chronic effects of PTH. Patients with primary hyperparathyroidism, a condition characterized by chronic elevations in PTH, exhibit persistent hypophosphatemia but not significant evidence of salt wasting. We postulate that chronic PTH stimulation results in differential desensitization of PTH responses. To address this hypothesis, we compared the effects of chronic PTH stimulation on Na-Pi cotransporter (Npt2a) expression and Na-K activity and expression in Sprague Dawley rats, transgenic mice featuring parathyroid-specific cyclin D1 overexpression (PTH-D1), and proximal tubule cell culture models. We demonstrated a progressive decrease in brush-border membrane (BBM) expression of Npt2a from rats treated with PTH for 6 h or 4 days, while Na-K expression and activity in the basolateral membranes (BLM) exhibited an initial decrease followed by recovery to control levels by 4 days. Npt2a protein expression in PTH-D1 mice was decreased relative to control animals, whereas levels of Na-K, NHERF-1, and PTH receptor remained unchanged. In PTH-D1 mice, NpT2a mRNA expression was reduced by 50% relative to control mice. In opossum kidney proximal tubule cells, PTH decreased Npt2a mRNA levels. Both actinomycin D and cycloheximide treatment prevented the PTH-mediated decrease in Npt2a mRNA, suggesting that the PTH response requires transcription and translation. These findings suggest that responses to chronic PTH exposure are selectively regulated at a posttranscriptional level. The persistence of the phosphaturic response to PTH occurs through posttranscriptional mechanisms.

Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat

2007 ◽  
Vol 292 (2) ◽  
pp. F861-F867 ◽  
Author(s):  
Melvin R. Hayden ◽  
Nazif A. Chowdhury ◽  
Shawna A. Cooper ◽  
Adam Whaley-Connell ◽  
Javad Habibi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Systolic Blood Pressure ◽  
Proximal Tubule ◽  
Structural Damage ◽  
Kidney Tissue ◽  
Proximal Tubule Cell ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

TG(mRen2)27 (Ren2) transgenic rats overexpress the mouse renin gene, with subsequent elevated tissue ANG II, hypertension, and nephropathy. The proximal tubule cell (PTC) is responsible for the reabsorption of 5–8 g of glomerular filtered albumin each day. Excess filtered albumin may contribute to PTC damage and tubulointerstitial disease. This investigation examined the role of ANG II-induced oxidative stress in PTC structural remodeling: whether such changes could be modified with in vivo treatment with ANG type 1 receptor (AT1R) blockade (valsartan) or SOD/catalase mimetic (tempol). Male Ren2 (6–7 wk old) and age-matched Sprague-Dawley rats were treated with valsartan (30 mg/kg), tempol (1 mmol/l), or placebo for 3 wk. Systolic blood pressure, albuminuria, N-acetyl-β-d-glucosaminidase, and kidney tissue malondialdehyde (MDA) were measured, and ×60,000 transmission electron microscopy images were used to assess PTC microvilli structure. There were significant differences in systolic blood pressure, albuminuria, lipid peroxidation (MDA and nitrotyrosine staining), and PTC structure in Ren2 vs. Sprague-Dawley rats (each P < 0.05). Increased mean diameter of PTC microvilli in the placebo-treated Ren2 rats ( P < 0.05) correlated strongly with albuminuria ( r2 = 0.83) and moderately with MDA ( r2 = 0.49), and there was an increase in the ratio of abnormal forms of microvilli in placebo-treated Ren2 rats compared with Sprague-Dawley control rats ( P < 0.05). AT1R blockade, but not tempol treatment, abrogated albuminuria and N-acetyl-β-d-glucosaminidase; both therapies corrected abnormalities in oxidative stress and PTC microvilli remodeling. These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria.

ER stress contributes to renal proximal tubule injury by increasing SREBP-2-mediated lipid accumulation and apoptotic cell death

2012 ◽  
Vol 303 (2) ◽  
pp. F266-F278 ◽  
Author(s):  
Šárka Lhoták ◽  
Sudesh Sood ◽  
Elise Brimble ◽  
Rachel E. Carlisle ◽  
Stephen M. Colgan ◽  
...  
Keyword(s):  
Er Stress ◽  
Proximal Tubule ◽  
Lipid Accumulation ◽  
Cell Injury ◽  
Apoptotic Cell ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Proximal Tubule Cells ◽  
Tubule Cells

Renal proximal tubule injury is induced by agents/conditions known to cause endoplasmic reticulum (ER) stress, including cyclosporine A (CsA), an immunosuppressant drug with nephrotoxic effects. However, the underlying mechanism by which ER stress contributes to proximal tubule cell injury is not well understood. In this study, we report lipid accumulation, sterol regulatory element-binding protein-2 (SREBP-2) expression, and ER stress in proximal tubules of kidneys from mice treated with the classic ER stressor tunicamycin (Tm) or in human renal biopsy specimens showing CsA-induced nephrotoxicity. Colocalization of ER stress markers [78-kDa glucose regulated protein (GRP78), CHOP] with SREBP-2 expression and lipid accumulation was prominent within the proximal tubule cells exposed to Tm or CsA. Prolonged ER stress resulted in increased apoptotic cell death of lipid-enriched proximal tubule cells with colocalization of GRP78, SREBP-2, and Ca2+-independent phospholipase A2 (iPLA2β), an SREBP-2 inducible gene with proapoptotic characteristics. In cultured HK-2 human proximal tubule cells, CsA- and Tm-induced ER stress caused lipid accumulation and SREBP-2 activation. Furthermore, overexpression of SREBP-2 or activation of endogenous SREBP-2 in HK-2 cells stimulated apoptosis. Inhibition of SREBP-2 activation with the site-1-serine protease inhibitor AEBSF prevented ER stress-induced lipid accumulation and apoptosis. Overexpression of the ER-resident chaperone GRP78 attenuated ER stress and inhibited CsA-induced SREBP-2 expression and lipid accumulation. In summary, our findings suggest that ER stress-induced SREBP-2 activation contributes to renal proximal tubule cell injury by dysregulating lipid homeostasis.

scholarly journals Proximal Tubule–Derived Amphiregulin Amplifies and Integrates Profibrotic EGF Receptor Signals in Kidney Fibrosis

2019 ◽  
Vol 30 (12) ◽  
pp. 2370-2383 ◽  
Author(s):  
Eirini Kefaloyianni ◽  
Manikanda Raja Keerthi Raja ◽  
Julian Schumacher ◽  
Muthu Lakshmi Muthu ◽  
Vaishali Krishnadoss ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Reperfusion Injury ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Proximal Tubule Cells ◽  
Kidney Fibrosis ◽  
Tubule Cells

BackgroundSustained activation of EGF receptor (EGFR) in proximal tubule cells is a hallmark of progressive kidney fibrosis after AKI and in CKD. However, the molecular mechanisms and particular EGFR ligands involved are unknown.MethodsWe studied EGFR activation in proximal tubule cells and primary tubular cells isolated from injured kidneys in vitro. To determine in vivo the role of amphiregulin, a low-affinity EGFR ligand that is highly upregulated with injury, we used ischemia-reperfusion injury or unilateral ureteral obstruction in mice with proximal tubule cell–specific knockout of amphiregulin. We also injected soluble amphiregulin into knockout mice with proximal tubule cell–specific deletion of amphiregulin’s releasing enzyme, the transmembrane cell-surface metalloprotease, a disintegrin and metalloprotease-17 (ADAM17), and into ADAM17 hypomorphic mice.ResultsYes-associated protein 1 (YAP1)–dependent upregulation of amphiregulin transcript and protein amplifies amphiregulin signaling in a positive feedback loop. YAP1 also integrates signals of other moderately injury-upregulated, low-affinity EGFR ligands (epiregulin, epigen, TGFα), which also require soluble amphiregulin and YAP1 to induce sustained EGFR activation in proximal tubule cells in vitro. In vivo, soluble amphiregulin injection sufficed to reverse protection from fibrosis after ischemia-reperfusion injury in ADAM17 hypomorphic mice; injected soluble amphiregulin also reversed the corresponding protective proximal tubule cell phenotype in injured proximal tubule cell–specific ADAM17 knockout mice. Moreover, the finding that proximal tubule cell–specific amphiregulin knockout mice were protected from fibrosis after ischemia-reperfusion injury or unilateral ureteral obstruction demonstrates that amphiregulin was necessary for the development of fibrosis.ConclusionsOur results identify amphiregulin as a key player in injury-induced kidney fibrosis and suggest therapeutic or diagnostic applications of soluble amphiregulin in kidney disease.

scholarly journals Therapeutic concentrations of calcineurin inhibitors do not deregulate glutathione redox balance in human renal proximal tubule cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250996
Author(s):  
Yasaman Ramazani ◽  
Noël Knops ◽  
Sante Princiero Berlingerio ◽  
Oyindamola Christiana Adebayo ◽  
Celien Lismont ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Cell Model ◽  
Calcineurin Inhibitors ◽  
Redox Balance ◽  
Solid Organ ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Proximal Tubule Cells ◽  
Tubule Cells ◽  
Glutathione Redox

The calcineurin inhibitors (CNI) cyclosporine A and tacrolimus comprise the basis of immunosuppressive regimes in all solid organ transplantation. However, long-term or high exposure to CNI leads to histological and functional renal damage (CNI-associated nephrotoxicity). In the kidney, proximal tubule cells are the only cells that metabolize CNI and these cells are believed to play a central role in the origin of the toxicity for this class of drugs, although the underlying mechanisms are not clear. Several studies have reported oxidative stress as an important mediator of CNI-associated nephrotoxicity in response to CNI exposure in different available proximal tubule cell models. However, former models often made use of supra-therapeutic levels of tissue drug exposure. In addition, they were not shown to express the relevant enzymes (e.g., CYP3A5) and transporters (e.g., P-glycoprotein) for the metabolism of CNI in human proximal tubule cells. Moreover, the used methods for detecting ROS were potentially prone to false positive results. In this study, we used a novel proximal tubule cell model established from human allograft biopsies that demonstrated functional expression of relevant enzymes and transporters for the disposition of CNI. We exposed these cells to CNI concentrations as found in tissue of stable solid organ transplant recipients with therapeutic blood concentrations. We measured the glutathione redox balance in this cell model by using organelle-targeted variants of roGFP2, a highly sensitive green fluorescent reporter protein that dynamically equilibrates with the glutathione redox couple through the action of endogenous glutaredoxins. Our findings provide evidence that CNI, at concentrations commonly found in allograft biopsies, do not alter the glutathione redox balance in mitochondria, peroxisomes, and the cytosol. However, at supra-therapeutic concentrations, cyclosporine A but not tacrolimus increases the ratio of oxidized/reduced glutathione in the mitochondria, suggestive of imbalances in the redox environment.

scholarly journals Proximal Tubule Cell Hypothesis for Cardiorenal Syndrome in Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Akihiko Saito ◽  
Ryohei Kaseda ◽  
Michihiro Hosojima ◽  
Hiroyoshi Sato
Keyword(s):  
Proximal Tubule ◽  
Cardiorenal Syndrome ◽  
Therapeutic Strategies ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Proximal Tubule Cells ◽  
Mineral Balance ◽  
Stage Renal Disease ◽  
End Stage ◽  
Mediate Metabolism

Incidence of cardiovascular disease (CVD) is remarkably high among patients with chronic kidney disease (CKD), even in the early microalbuminuric stages with normal glomerular filtration rates. Proximal tubule cells (PTCs) mediate metabolism and urinary excretion of vasculotoxic substances via apical and basolateral receptors and transporters. These cells also retrieve vasculoprotective substances from circulation or synthesize them for release into the circulation. PTCs are also involved in the uptake of sodium and phosphate, which are critical for hemodynamic regulation and maintaining the mineral balance, respectively. Dysregulation of PTC functions in CKD is likely to be associated with the development of CVD and is linked to the progression to end-stage renal disease. In particular, PTC dysfunction occurs early in diabetic nephropathy, a leading cause of CKD. It is therefore important to elucidate the mechanisms of PTC dysfunction to develop therapeutic strategies for treating cardiorenal syndrome in diabetes.

Ca and P regulation of 1,25(OH)2D3 synthesis by vitamin D-replete rat tubules during acidosis

1986 ◽  
Vol 251 (5) ◽  
pp. F911-F918 ◽  
Author(s):  
C. B. Langman ◽  
D. A. Bushinsky ◽  
M. J. Favus ◽  
F. L. Coe
Keyword(s):  
Vitamin D ◽  
Proximal Tubule ◽  
Phosphorus Concentration ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Short Term ◽  
Medium Ph ◽  
Dihydroxyvitamin D3 ◽  
Proximal Tubule Cells

Elevated blood ionized Ca concentration appears to be necessary for suppression by chronic metabolic acidosis (CMA) of serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels in vitamin D-replete rats eating a low-Ca diet (LCD). The present study asks whether in vitro 1,25(OH)2D3 production by proximal tubule cells from such rats is suppressed and whether suppression can be reversed in vitro by an altered ionic milieu. Young rats were fed LCD and given 1.5% NH4Cl in their drinking water for 10 days to produce CMA. Compared with controls, CMA rats had low serum 1,25(OH)2D3 levels. Tubules prepared from CMA rats produced 1,25(OH)2D3 at a low rate compared with control; variation of medium Ca and pH from 7.2 to 7.4 did not increase 1,25(OH)2D3 production. Reducing medium phosphorus concentration ([P]) increased 1,25(OH)2D3 production by tubules from control but not CMA rats. Increasing medium [P] increased 1,25(OH)2D3 production by tubules from CMA but not control rats. CMA appears to alter proximal tubule cell response to medium [P] so that 1,25(OH)2D3 production rises when medium [P] is increased but not when it is reduced. Medium pH and Ca concentration do not appear to be important regulators of renal 1,25(OH)2D3 production in short-term incubations.

Electroacupuncture at Zusanli Rescues the Enteric Neuronal Loss in the Stomach of Diabetic Rats

2012 ◽  
Vol 18 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Min Hu ◽  
Fan Du ◽  
Shi Liu
Keyword(s):  
High Frequency ◽  
Low Frequency ◽  
Neuronal Loss ◽  
Diabetic Rats ◽  
Enteric Neurons ◽  
Control Group ◽  
Sprague Dawley ◽  
Long Duration ◽  
Sprague Dawley Rats ◽  
Zusanli Acupoint

The purpose of this study was to investigate the effects of electroacupuncture at Zusanli acupoint on the enteric neuropathy in diabetic rats. Sprague–Dawley rats were divided into different groups depending on the total electroacupuncture span and frequency. The expression of nitric oxide synthase (nNOS), choline acetyltransferase (CHAT), protein gene product 9.5 (PGP9.5), and doublecortin was significantly decreased in the diabetic group compared with the control group. Long-term electroacupuncture at Zusanli with either high frequency or low frequency could increase the expression levels of nNOS, CHAT, PGP9.5, and doublecortin, and the increase was greater in the high-frequency group. But no obvious changes were seen in the short-term electroacupuncture groups. These results suggest that electroacupuncture at Zusanli can restore the deficiency of enteric neurons in diabetes partly but a comparative long duration of stimuli (6 weeks) is required. The increase of doublecortin may be involved in this positive process.

scholarly journals THE POLARITY OF THE PROXIMAL TUBULE CELL IN RAT KIDNEY

1972 ◽  
Vol 54 (2) ◽  
pp. 232-245 ◽  
Author(s):  
Hans-G Heidrich ◽  
Rolf Kinne ◽  
Eva Kinne-Saffran ◽  
Kurt Hannig
Keyword(s):  
Proximal Tubule ◽  
Plasma Membranes ◽  
Specific Activity ◽  
Rat Kidney ◽  
High Specific Activity ◽  
Kidney Cortex ◽  
Proximal Tubule Cell ◽  
Surface Charges ◽  
Tubule Cell ◽  
Rat Kidney Cortex

Two different membrane fractions were obtained from a brush-border fraction of rat kidney cortex by using their different electrical surface charges in preparative free-flow electrophoresis. One membrane fraction contained only morphologically intact microvilli and was characterized by a high specific activity of alkaline phosphatase. The other fraction morphologically resembled classical plasma membranes by possessing junctional complexes and a high Na-K-ATPase activity The contamination of the isolated membrane fractions by other cell organelles was extremely low These two fractions represent the apical (luminal) and the basal (interstitial) area of the renal proximal tubule cell membrane and clearly demonstrate the polarity of this cell.

KELULUT HONEY SUPPLEMENTATION PREVENTS SPERM AND TESTICULAR OXIDATIVE DAMAGE IN STREPTOZOTOCIN-INDUCED DIABETIC RATS

2017 ◽  
Vol 79 (3) ◽  
Author(s):  
Siti Balkis Budin ◽  
Fatin Farhana Jubaidi ◽  
Siti Nur Farahana Mohd Noor Azam ◽  
Nur Liyana Mohamed Yusof ◽  
Izatus Shima Taib ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Sperm Quality ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Control Groups ◽  
Sod Activity ◽  
Male Adult ◽  
Pathological Conditions ◽  
Sprague Dawley Rats

Previous studies found that Kelulut Honey produced by Trigona spp. bees is able to prevent oxidative damage in various pathological conditions.  Thus, the present study aimed to determine whether Kelulut Honey could prevent the sperm and testicular damage in streptozotocin-induced diabetic rats. Male Adult male Sprague-Dawley rats were divided into four groups: Non-Diabetic (NDM), Non-Diabetic with Kelulut Honey supplementation (NDMKH), Diabetic without supplementation (DM) and Diabetic with Kelulut Honey supplementation (DMKH).  Kelulut honey was given at the dose of 2.0 g/kg weight daily via gavage for 28 consecutive days. Results showed that sperm quality produced by diabetic rats supplemented with Kelulut honey significantly improved compared to the diabetic control groups (p<0.05). SOD activity and GSH level increased significantly (p<0.05) whereas PC and MDA levels significantly decreased in sperm and testis of DMKH rats when compared to DM rats (p<0.05). Histological observation showed obvious increase in spermatozoa in the lumen of epididymis and increased spermatogenic cells density in the testis of DMKH group.  In conclusion, Kelulut Honey has a potential in preventing the damage of sperm and testis in diabetic rats.

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