31 results on '"Malgorzata Kasztan"'
Search Results
2. Timing of Food Intake Drives the Circadian Rhythm of Blood Pressure
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Dingguo Zhang, Paramita Pati, Thomas H. Neder, Malgorzata Kasztan, Jennifer S. Pollock, Jennifer A Valcin, Binli Tao, Karen L. Gamble, Bryan K. Becker, Jodi R. Paul, Chunhua Jin, Jackson Colson, David M. Pollock, Megan K Rhoads, McKenzi A King, and Shannon M. Bailey
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Male ,0301 basic medicine ,time-restricted feeding ,medicine.medical_specialty ,Mean arterial pressure ,Renal cortex ,Period (gene) ,030204 cardiovascular system & hematology ,Mice ,Eating ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Circadian rhythm ,Original Research ,Mice, Knockout ,Suprachiasmatic nucleus ,business.industry ,Sodium ,ARNTL Transcription Factors ,blood pressure ,Circadian Rhythm ,Mice, Inbred C57BL ,PER2 ,Bmal1 ,030104 developmental biology ,Blood pressure ,Endocrinology ,medicine.anatomical_structure ,circadian rhythms ,Renal physiology ,AcademicSubjects/SCI00960 ,sodium excretion ,business ,Research Article - Abstract
Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure (BP) and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-h lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 mmHg vs 100 ± 2 mmHg, respectively; P 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 mmHg vs 95 ± 2 mmHg, lights-off vs lights-on phase; P, Graphical Abstract Graphical Abstract
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- 2020
3. Role for ovarian hormones in purinoceptor-dependent natriuresis
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Edward W. Inscho, Malgorzata Kasztan, Eman Y. Gohar, Shali Zhang, and David M. Pollock
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Epithelial sodium channel ,Male ,medicine.medical_specialty ,Purinoceptors ,Ovariectomy ,Natriuresis ,lcsh:Medicine ,Suramin ,lcsh:Physiology ,Cell Line ,Gender Studies ,Rats, Sprague-Dawley ,Receptors, Purinergic P2Y2 ,Endocrinology ,Sex Factors ,Internal medicine ,medicine ,Renal medulla ,Animals ,RNA, Messenger ,Receptor ,Epithelial Sodium Channels ,Sodium excretion ,Kidney Medulla ,Phospholipase C ,Dose-Response Relationship, Drug ,Estradiol ,lcsh:QP1-981 ,Chemistry ,Receptors, Purinergic P2 ,Research ,Purinergic receptor ,Ovary ,lcsh:R ,Rats ,medicine.anatomical_structure ,Gene Expression Regulation ,Type C Phospholipases ,Ovariectomized rat ,Female ,Hormone - Abstract
Background: Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y2 and P2Y4 purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na+ transport. Activation of these receptors inhibits epithelial Na+ channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y2 and P2Y4 receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y2 and P2Y4) receptors regulating Na+ excretion compared to male and OVX rats. Methods: To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na+ excretion in anesthetized male, ovary-intact female and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y2 and P2Y4 receptors and (iii) mRNA expression of their downstream effectors (PLC-1d and ENaCa) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E2, 0, 10, 100 and 1000 nM) to test whether E2 increases mRNA expression of P2Y2 and P2Y4 receptors.Results: Acute P2 inhibition attenuated urinary Na+ excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y2 and P2Y4 mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y2 receptor protein abundance, compared to males, however, OVX did not eliminate this sex difference. We also found that E2 dose-dependently upregulated P2Y2 and P2Y4 mRNA expression in mIMCD3. Conclusion: These data suggest that ovary-intact females have enhanced P2Y2 and P2Y4-dependent regulation of Na+ handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na+ handling in premenopausal females.
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- 2020
4. Abstract P063: Pressor Response To Acute Stress Is Regulated By Histamine In Humanized Sickle Cell Mice
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David M. Pollock, Malgorzata Kasztan, Bryan K. Becker, Patrick Molina, Brandon M. Fox, Davide Botta, John Miller Allan, Randee Sedaka, and Jennifer S. Pollock
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business.industry ,Vascular disease ,Cell ,Disease ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,Pressor response ,chemistry ,Psychosocial stress ,Immunology ,Internal Medicine ,medicine ,In patient ,Acute stress ,business ,Histamine - Abstract
Acute psychosocial stress has been linked to the onset of vaso-occlusive pain crises in patients with sickle cell disease (SCD), however mechanistic insight is lacking. Studies suggest that histamine is a stress-responsive factor and promotes inflammation. In SCD, histamine levels are elevated in association with vaso-occulsive crisis, however, the impact of acute stress is unknown. We hypothesized that acute stress in a humanized SCD mouse model stimulates the histamine pathway, inflammatory mediator release, and a pressor response. Acute stress was induced using cage switch stress (CSS) in male humanized SCD (HbSS) or control (HbAA) mice (n=6-8/group) with blood pressure (BP) monitored by radiotelemetry and mice terminated at baseline (BL, no CSS) and 30 min post-CSS for plasma measurements. Plasma histamine was unchanged in HbAA mice but was elevated in HbSS in response to CSS (nM; HbAA: 90.2±21.3; 104.3±10.2; HbSS: 91.1±13.6; 174.3±19.2*, *pgenotype =0.0001, *pgenotype genotype
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- 2020
5. Diurnal Control of Blood Pressure Is Uncoupled From Sodium Excretion
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Megan K Rhoads, Malgorzata Kasztan, Joshua S. Speed, Reham H Soliman, Binli Tao, Jermaine G. Johnston, Bryan K. Becker, Kelly A. Hyndman, Aron M. Geurts, Chunhua Jin, David M. Pollock, and Jennifer S. Pollock
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0301 basic medicine ,Male ,medicine.medical_specialty ,Mean arterial pressure ,endocrine system ,Knockout rat ,Sodium ,Period (gene) ,chemistry.chemical_element ,Blood Pressure ,030204 cardiovascular system & hematology ,Kidney ,Article ,Animals, Genetically Modified ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Sex Factors ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Circadian rhythm ,ARNTL Transcription Factors ,Circadian Rhythm ,Rats ,CLOCK ,Renal Elimination ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Blood pressure ,chemistry ,Female - Abstract
The diurnal rhythms of sodium handling and blood pressure are thought to be regulated by clock genes, such as Bmal1. However, little is known about the regulation of these factors by Bmal1, especially in rats. Using a novel whole-body Bmal1 knockout rat model ( Bmal1 − /− ), we hypothesized that time of day regulation of sodium excretion is dependent on Bmal1. Using telemetry to continuously record mean arterial pressure, we observed that male and female Bmal1 −/− rats had significantly reduced mean arterial pressure over the course of 24 hours compared with littermate controls. The circadian mean arterial pressure pattern remained intact in both sexes of Bmal1 −/− rats, which is in contrast to the Bmal1 −/− mouse model. Male Bmal1 −/− rats had no significant difference in baseline sodium excretion between 12-hour active and inactive periods, indicating a lack of diurnal control independent of maintained mean arterial pressure rhythms. Female Bmal1 −/− rats, however, had significantly greater sodium excretion during the active versus inactive period similar to controls. Thus, we observed a clear dissociation between circadian blood pressure and control of sodium excretion that is sex dependent. These findings are consistent with a more robust ability of females to maintain control of sodium excretion, and furthermore, demonstrate a novel role for Bmal1 in control of diurnal blood pressure independent of sodium excretion.
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- 2020
6. High dietary sodium causes dyssynchrony of the renal molecular clock in rats
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Martin E. Young, Kaehler J. Roth, Jennifer S. Pollock, Jonathan Brett Heimlich, Joshua S. Speed, Malgorzata Kasztan, David M. Pollock, Brandon M. Fox, Jermaine G. Johnston, Karen L. Gamble, Bryan K. Becker, Kelly A. Hyndman, and Chunhua Jin
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Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Sodium ,CLOCK Proteins ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Biology ,Kidney ,03 medical and health sciences ,0302 clinical medicine ,Dietary Sodium ,Internal medicine ,Cell autonomous ,medicine ,Animals ,Circadian rhythm ,Sodium Chloride, Dietary ,Molecular clock ,Endothelins ,Sodium, Dietary ,Feeding Behavior ,Period Circadian Proteins ,Circadian Rhythm ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Research Article - Abstract
Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89–F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.—Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ETB) receptor functions to facilitate Na+ excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ETB-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na+ channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ETB receptors within the renal inner medulla.
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- 2018
7. P-Selectin Deficiency Reduces Acute Vascular Complications but Not Chronic Organ Damage in Sickle Cell Mice
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Rafal Pawlinski, Brandi Reeves, Prithu Sundd, Megan D Miller, Christina M Abrams, Erica M. Sparkenbaugh, Elizabeth A Binning, and Malgorzata Kasztan
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Organ damage ,Pathology ,medicine.medical_specialty ,medicine.anatomical_structure ,P-selectin ,business.industry ,Immunology ,Cell ,medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
P-selectin (Psel) is an adhesion molecule expressed on platelets and endothelial cells, which interacts with its ligand PSGL-1 on leukocytes and a PSGL-1-like molecule on sickle red blood cells (RBCs). Psel mediates the formation of the multicellular aggregates that promote vaso-occlusive crisis (VOC) and acute painful episodes in sickle cell disease (SCD). Crizanlizumab, a monoclonal antibody blocking Psel, reduces the frequency of VOC in SCD patients. In SCD mice, Psel contributes to heme-induced microvascular stasis, and thrombus and platelet-neutrophil aggregate formation in the lung and liver. Unexpectedly, Psel deficiency promotes liver senescence in a mouse model of SCD, suggesting a possible detrimental effect of Psel inhibition. In this study, we further investigated the long-term effects of Psel deficiency on thromboinflammation and end-organ damage in murine SCD. We used Townes wild type (AA) and sickle (SS) mice (n=12-27) that either express Psel (Psel +/+) or lack Psel (Psel -/-) at 11-12 months of age. Kidney damage was evaluated by histology and urine analysis. Heart function was determined using echocardiography. Complete blood counts and plasma biomarkers of thrombin generation (thrombin anti-thrombin [TAT] complexes) and inflammation (interleukin [IL]-6) were also analyzed. In addition, in a pilot experiment, we analyzed the effect of Psel deficiency on experimental venous thrombosis in SS mice. SS Psel +/+ mice exhibited renal damage, urinary concentrating defect, and reduced creatinine clearance, which was not improved in SS Psel -/- mice. Psel deficiency attenuated glomerular (GLM) congestion (0.17±0.05 vs 0.39±0.06, p We observed cardiac hypertrophy (elevated heart weight to tibia length ratio) in SS mice, regardless of Psel expression. Echocardiography of left ventricle (LV) revealed that SS mice had increased LV mass and LV internal diameter with no change in ejection fraction or fractional shortening compared to AA mice. None of these parameters were affected by Psel expression. Furthermore, hypertrophy observed in other organs (kidney, liver, lung and spleen) of SS Psel +/+ mice was also not affected by Psel deficiency. Consistent with previous studies, SS Psel +/+ mice had elevated plasma levels of TAT and IL-6 compared to AA Psel +/+ mice. Psel deficiency significantly reduced IL-6 (47±15 vs 20±10 ng/mL, P As expected, SS Psel +/+ mice exhibited anemia as shown by reduced RBC number, hemoglobin (Hb) and hematocrit (Hct) compared to AA Psel +/+ animals. Interestingly, these parameters were further decreased in SS Psel -/- mice (p Our data suggest that despite improving acute vascular pathologies, including VOC and thromboinflammation, long term deficiency of Psel does not prevent end-organ damage. If fact, it may contribute to organ dysfunction and enhanced anemia. More mechanistic studies are needed to better understand the long-term effects of anti-Psel treatment in SCD patients. Disclosures Reeves: Incyte Corporation: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Pharma Essentia: Consultancy, Honoraria. Sundd: CSL Behring Inc: Research Funding; Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2021
8. Renal denervation attenuates hypertension but not salt sensitivity in ETB receptor-deficient rats
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Bryan K. Becker, Jennifer S. Pollock, Joshua S. Speed, Chunhua Jin, David M. Pollock, Daian Chen, Malgorzata Kasztan, and Amanda C. Feagans
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Denervation ,medicine.medical_specialty ,Sympathetic nervous system ,Kidney ,Mean arterial pressure ,Vasomotor ,Physiology ,business.industry ,030204 cardiovascular system & hematology ,Baroreflex ,03 medical and health sciences ,Parasympathetic nervous system ,0302 clinical medicine ,medicine.anatomical_structure ,Blood pressure ,Endocrinology ,Physiology (medical) ,Internal medicine ,medicine ,business ,030217 neurology & neurosurgery - Abstract
Hypertension is a prevalent pathology that increases risk for numerous cardiovascular diseases. Because the etiology of hypertension varies across patients, specific and effective therapeutic approaches are needed. The role of renal sympathetic nerves is established in numerous forms of hypertension, but their contribution to salt sensitivity and interaction with factors such as endothelin-1 are poorly understood. Rats deficient of functional ETB receptors (ETB-def) on all tissues except sympathetic nerves are hypertensive and exhibit salt-sensitive increases in blood pressure. We hypothesized that renal sympathetic nerves contribute to hypertension and salt sensitivity in ETB-def rats. The hypothesis was tested through bilateral renal sympathetic nerve denervation and measuring blood pressure during normal salt (0.49% NaCl) and high-salt (4.0% NaCl) diets. Denervation reduced mean arterial pressure in ETB-def rats compared with sham-operated controls by 12 ± 3 (SE) mmHg; however, denervation did not affect the increase in blood pressure after 2 wk of high-salt diet (+19 ± 3 vs. +16 ± 3 mmHg relative to normal salt diet; denervated vs. sham, respectively). Denervation reduced cardiac sympathetic-to-parasympathetic tone [low frequency-high frequency (LF/HF)] during normal salt diet and vasomotor LF/HF tone during high-salt diet in ETB-def rats. We conclude that the renal sympathetic nerves contribute to the hypertension but not to salt sensitivity of ETB-def rats.
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- 2017
9. Ovariectomy uncovers purinergic receptor activation of endothelin-dependent natriuresis
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Malgorzata Kasztan, Eman Y. Gohar, David M. Pollock, Bryan K. Becker, and Joshua S. Speed
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Endothelin Receptor Antagonists ,Purinergic P2 Receptor Agonists ,0301 basic medicine ,medicine.medical_specialty ,Time Factors ,Physiology ,Ovariectomy ,Natriuresis ,Sodium Chloride ,Rats, Sprague-Dawley ,Receptors, Purinergic P2Y2 ,03 medical and health sciences ,Internal medicine ,Male rats ,Purinergic P2 Receptor Antagonists ,medicine ,Renal medulla ,Animals ,Receptor ,Salt loading ,Kidney Medulla ,Endothelin-1 ,Receptors, Purinergic P2 ,Chemistry ,Sodium ,Purinergic receptor ,Endothelin 1 ,Renal Elimination ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Female ,Endothelin receptor ,Signal Transduction ,Research Article - Abstract
We recently reported that natriuresis produced by renal medullary salt loading is dependent on endothelin (ET)-1 and purinergic (P2) receptors in male rats. Because sex differences in ET-1 and P2 signaling have been reported, we decided to test whether ovarian sex hormones regulate renal medullary ET-1 and P2-dependent natriuresis. The effect of medullary NaCl loading on Na+excretion was determined in intact and ovariectomized (OVX) female Sprague-Dawley rats with and without ET-1 or P2 receptor antagonism. Isosmotic saline (284 mosmol/kgH2O) was infused in the renal medullary interstitium of anesthetized rats during a baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgH2O) infusion. Medullary NaCl loading significantly enhanced Na+excretion in intact and OVX female rats. ETA+Bor P2 receptor blockade did not attenuate the natriuretic effect of medullary NaCl loading in intact females, whereas ETA+Bor P2 receptor blockade attenuated the natriuretic response to NaCl loading in OVX rats. Activation of medullary P2Y2and P2Y4receptors by UTP infusion had no significant effect in intact females but enhanced Na+excretion in OVX rats. Combined ETA+Breceptor blockade significantly inhibited the natriuretic response to UTP observed in OVX rats. These data demonstrate that medullary NaCl loading induces ET-1 and P2-independent natriuresis in intact females. In OVX, activation of medullary P2 receptors promotes ET-dependent natriuresis, suggesting that ovarian hormones may regulate the interplay between the renal ET-1 and P2 signaling systems to facilitate Na+excretion.
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- 2017
10. Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice
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Abdullah Kutlar, Jennifer S. Pollock, Carmen De Miguel, Eman Y. Gohar, Tim M. Townes, Joshua S. Speed, Brandon M. Fox, Malgorzata Kasztan, and David M. Pollock
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0301 basic medicine ,medicine.medical_specialty ,Ambrisentan ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Podocyte ,Nephropathy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Receptor ,business.industry ,Glomerulosclerosis ,General Medicine ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Nephrology ,Humanized mouse ,Albuminuria ,medicine.symptom ,business ,Endothelin receptor ,medicine.drug - Abstract
Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.
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- 2017
11. Abstract P1107: Acute Psychosocial Stress Increases Circulating Inflammatory Mediators in the Humanized Sickle Cell Mouse Model
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Davide Botta, Malgorzata Kasztan, Jennifer S. Pollock, Bryan K. Becker, David M. Pollock, Randee Sedaka, J. Miller Allan, Brandon M. Fox, and Patrick Molina
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business.industry ,Cell ,Inflammation ,Disease ,Blood pressure ,medicine.anatomical_structure ,Immunology ,Psychosocial stress ,otorhinolaryngologic diseases ,Internal Medicine ,medicine ,medicine.symptom ,business ,Vascular function - Abstract
Vaso-occlusive crisis often occurs in sickle cell disease (SCD). Since psychosocial stress leads to impaired vascular function and inflammation, we hypothesized that acute psychosocial stress elicits an exaggerated blood pressure response and/or increased circulating inflammatory mediators in a mouse model of SCD. We utilized adult male (16-20 wks) humanized Townes sickle cell (HbSS) and control (HbAA) mice with telemetry (n=8) to monitor changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), spectral analysis (low frequency/high frequency, LF/HF ratio) of blood pressure variability, heart rate (HR), and locomotor activity (LA) in response to cage switch stress (CSS). CSS-induced increases in DBP were significantly attenuated in HbSS versus HbAA (HbSS: 23.3±1.8mmHg, HbAA: 31.6±1.7mmHg, p=0.004), while the increase in SBP was similar in HbSS and HbAA. CSS increased LF/HF in both strains, although HbSS was significantly less than HbAA (CSS HbAA : 3.21±0.2; CSS HbSS : 1.68±0.2, p
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- 2019
12. Hyperfiltration predicts long-term renal outcomes in humanized sickle cell mice
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Brandon M. Fox, Joshua S. Speed, Jennifer S. Pollock, Malgorzata Kasztan, Kelly A. Hyndman, Jeffrey D. Lebensburger, and David M. Pollock
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Male ,medicine.medical_specialty ,Anemia ,Transgene ,Cell ,Hemoglobin, Sickle ,Renal function ,Mice, Transgenic ,Disease ,Anemia, Sickle Cell ,030204 cardiovascular system & hematology ,Kidney ,Nephropathy ,Excretion ,Kidney Tubules, Proximal ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Red Cells, Iron, and Erythropoiesis ,Internal medicine ,medicine ,Animals ,Humans ,Hepatitis A Virus Cellular Receptor 1 ,Longitudinal Studies ,Child ,business.industry ,Membrane Proteins ,Hematology ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Commentary ,Kidney Diseases ,Female ,business ,030215 immunology ,Glomerular Filtration Rate - Abstract
We previously reported that humanized sickle cell (HbSS) mice develop spontaneous nephropathy, a major cause of morbidity and mortality in sickle cell disease (SCD). Because sex-dependent protective mechanisms in SCD have been reported, we examined the course of nephropathy in male and female HbSS mice to determine contributors and/or predictors of disease severity. In male HbSS mice, glomerular filtration rate was characterized by a rapid onset of hyperfiltration and subsequent progressive decline of renal function over 20 weeks. Early tubular injury presented with increased excretion of kidney injury marker 1 (KIM-1), progressive loss of tubular brush border, and interstitial fibrosis that preceded the onset of glomerular damage, suggesting a tubuloglomerular mechanism of kidney injury in these mice. Additionally, we observed a strong association between the magnitude of hyperfiltration and the degree of long-term kidney injury in male HbSS mice. Unlike males, female HbSS mice did not demonstrate a significant loss of renal function or severe kidney damage during the time course of the study. These results suggest that magnitude of hyperfiltration predicts the onset of chronic kidney damage in male HbSS mice, whereas protective mechanisms in female HbSS mice delay the onset of SCD nephropathy.
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- 2019
13. Glomerular hyperfiltration predicts the onset of chronic kidney disease in humanized sickle cell mice
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Joshua S. Speed, Malgorzata Kasztan, and David M. Pollock
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Pathology ,medicine.medical_specialty ,business.industry ,Cell ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Genetics ,medicine ,business ,Molecular Biology ,Glomerular hyperfiltration ,Biotechnology ,Kidney disease - Published
- 2019
14. Renal T H 17 cells are Elevated in Humanized Sickle Cell Mice
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Patrick A. Molina, Davide Botta, Carmen De Miguel, Jennifer S. Pollock, Malgorzata Kasztan, David M. Pollock, Brandon M. Fox, Fengyuan Huang, and Ryan J. McMonigle
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medicine.anatomical_structure ,Chemistry ,Cell ,Genetics ,medicine ,Molecular Biology ,Biochemistry ,Molecular biology ,Biotechnology - Published
- 2019
15. Dynamic changes in histone deacetylases following kidney ischemia-reperfusion injury are critical for promoting proximal tubule proliferation
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Kelly A. Hyndman, Luciano D. Mendoza, Malgorzata Kasztan, and Sureena Monteiro-Pai
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Male ,Pathology ,medicine.medical_specialty ,Time Factors ,Physiology ,Inflammation ,Histone Deacetylases ,Cell Line ,Kidney Tubules, Proximal ,Fibrosis ,medicine ,Autophagy ,Animals ,Cell Proliferation ,biology ,Renal ischemia ,business.industry ,urogenital system ,Acute kidney injury ,Epithelial Cells ,Acute Kidney Injury ,medicine.disease ,Rats ,Histone Deacetylase Inhibitors ,Mice, Inbred C57BL ,Disease Models, Animal ,Histone ,medicine.anatomical_structure ,Reperfusion Injury ,biology.protein ,Proximal tubule ,Histone deacetylase ,medicine.symptom ,business ,Reperfusion injury ,Signal Transduction ,Research Article - Abstract
Deranged histone deacetylase (HDAC) activity causes uncontrolled proliferation, inflammation, fibrosis, and organ damage. It is unclear whether deranged HDAC activity results in acute kidney injury in the renal hypoperfusion model of bilateral ischemia-reperfusion injury (IRI) and whether in vivo inhibition is an appropriate therapeutic approach to limit injury. Male mice were implanted with intraperitoneal osmotic minipumps containing vehicle, the class I HDAC inhibitor, MS275, or the pan-HDAC inhibitor, trichostatin A (TSA), 3 days before sham/bilateral IRI surgery. Kidney cortical samples were analyzed using histological, immunohistochemical, and Western blotting techniques. HDAC-dependent proliferation rate was measured in immortalized rat epithelial cells and primary mouse or human proximal tubule (PT) cells. There were dynamic changes in cortical HDAC localization and abundance following IRI including a fourfold increase in HDAC4 in the PT. HDAC inhibition resulted in a significantly higher plasma creatinine, increased kidney damage, but reduced interstitial fibrosis compared with vehicle-treated IRI mice. HDAC-inhibited mice had reduced interstitial α-smooth muscle actin, fibronectin expression, and Sirius red-positive area, suggesting that IRI activates HDAC-mediated fibrotic pathways. In vivo proliferation of the kidney epithelium was significantly reduced in TSA-treated, but not MS275-treated, IRI mice, suggesting class II HDACs mediate proliferation. Furthermore, HDAC4 activation increased proliferation of human and mouse PTs. Kidney HDACs are activated during IRI with isoform-specific expression patterns. Our data point to mechanisms whereby IRI activates HDACs resulting in fibrotic pathways but also activation of PT proliferation and repair pathways. This study demonstrates the need to develop isoform-selective HDAC inhibitors for the treatment of renal hypoperfusion-induced injury.
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- 2019
16. Impact of ET-1 and sex in glomerular hyperfiltration in humanized sickle cell mice
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Malgorzata Kasztan and David M. Pollock
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0301 basic medicine ,Male ,medicine.medical_specialty ,Endothelin A Receptor Antagonists ,Cell ,Kidney Glomerulus ,Renal function ,Mice, Transgenic ,Anemia, Sickle Cell ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,Sex Factors ,Risk Factors ,Diabetes mellitus ,Internal medicine ,medicine ,Animals ,Humans ,Receptor ,Endothelin-1 ,Phenylpropionates ,business.industry ,Glomerular permeability ,Antagonist ,Hemoglobin A ,General Medicine ,medicine.disease ,Endothelin 1 ,Pyridazines ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Mutation ,Female ,Kidney Diseases ,business ,Glomerular hyperfiltration ,Glomerular Filtration Rate ,Signal Transduction - Abstract
Hyperfiltration, highly prevalent early in sickle cell disease (SCD), is in part driven by an increase in ultrafiltration coefficient (Kf). The increase in Kf may be due to enlarged filtration surface area and/or increased glomerular permeability (Palb). Previous studies have demonstrated that endothelin-1 (ET-1) contributes to Palb changes in models of diabetes and SCD. Thus, we performed longitudinal studies of renal function to determine the relationship between ET-1 and glomerular size and Palb that may contribute to hyperfiltration in humanized sickle cell (HbSS) and control (HbAA) mice at 8–32 weeks of age. HbSS mice were characterized by significant increases in plasma and glomerular ET-1 expression in both sexes although this increase was significantly greater in males. HbSS glomeruli of both males and females presented with a progressive and significant increase in glomerular size, volume, and Kf. During the onset of hyperfiltration, plasma and glomerular ET-1 expression were associated with a greater increase in glomerular size and Kf in HbSS mice, regardless of sex. The pattern of Palb augmentation during the hyperfiltration was also associated with an increase in glomerular ET-1 expression, in both male and female HbSS mice. However, the increase in Palb was significantly greater in males and delayed in time in females. Additionally, selective endothelin A receptor (ETA) antagonist prevented hyperfiltration in HbSS, regardless of sex. These results suggest that marked sex disparity in glomerular hyperfiltration may be driven, in part, by ET-1-dependent ultra-structural changes in filtration barrier components contributing to glomerular hyperfiltration in HbSS mice.
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- 2019
17. Activation of purinergic receptors (P2) in the renal medulla promotes endothelin-dependent natriuresis in male rats
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David M. Pollock, Chunhua Jin, Eman Y. Gohar, Malgorzata Kasztan, and Joshua S. Speed
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Male ,Purinergic P2 Receptor Agonists ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Natriuresis ,Uridine Triphosphate ,Sodium Chloride ,Rats, Sprague-Dawley ,03 medical and health sciences ,Internal medicine ,Purinergic P2 Receptor Antagonists ,Renal medulla ,medicine ,Animals ,Kidney Medulla ,Kidney ,Endothelin-1 ,Chemistry ,Reabsorption ,Osmolar Concentration ,Sodium ,Purinergic receptor ,Purinergic signalling ,Receptor, Endothelin A ,Receptor, Endothelin B ,Endothelin 1 ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Call for Papers ,Potassium ,Endothelin receptor ,Receptors, Purinergic P2X4 - Abstract
Renal endothelin-1 (ET-1) and purinergic signaling systems regulate Na+reabsorption in the renal medulla. A link between the renal ET-1 and purinergic systems was demonstrated in vitro, however, the in vivo interaction between these systems has not been defined. To test whether renal medullary activation of purinergic (P2) receptors promotes ET-dependent natriuresis, we determined the effect of increased medullary NaCl loading on Na+excretion and inner medullary ET-1 mRNA expression in anesthetized adult male Sprague-Dawley rats in the presence and absence of purinergic receptor antagonism. Isosmotic saline (NaCl; 284 mosmol/kgH2O) was infused into the medullary interstitium (500 μl/h) during a 30-min baseline urine collection period, followed by isosmotic or hyperosmotic saline (1,800 mosmol/kgH2O) for two further 30-min urine collection periods. Na+excretion was significantly increased during intramedullary infusion of hyperosmotic saline. Compared with isosmotic saline, hyperosmotic saline infused into the renal medulla caused significant increases in inner medullary ET-1 mRNA expression. Renal intramedullary infusion of the P2 receptor antagonist suramin inhibited the increase in Na+excretion and inner medullary ET-1 mRNA expression induced by NaCl loading in the renal medulla. Activation of medullary P2Y2/4receptors by infusion of UTP increased urinary Na+excretion. Combined ETAand ETBreceptor blockade abolished the natriuretic response to intramedullary infusion of UTP. These data demonstrate that activation of medullary P2 receptors promotes ET-dependent natriuresis in male rats, suggesting that the renal ET-1 and purinergic signaling systems interact to efficiently facilitate excretion of a NaCl load.
- Published
- 2016
18. Intracellular calcium signaling regulates glomerular filtration barrier permeability: the role of the PKGIα-dependent pathway
- Author
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Stefan Angielski, Irena Audzeyenka, Dorota Rogacka, Malgorzata Kasztan, Agnieszka Piwkowska, and Maciej Jankowski
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Biophysics ,chemistry.chemical_element ,Calcium ,Biology ,Biochemistry ,Calcium in biology ,Podocyte ,Plasma Membrane Calcium-Transporting ATPases ,03 medical and health sciences ,Structural Biology ,Internal medicine ,Genetics ,medicine ,Animals ,Calcium Signaling ,Molecular Biology ,Cyclic GMP-Dependent Protein Kinase Type I ,Calcium signaling ,Podocytes ,Endoplasmic reticulum ,Cell Biology ,Rats ,Cell biology ,Calcium ATPase ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Glomerular Filtration Barrier ,Protein Multimerization ,cGMP-dependent protein kinase ,Glomerular Filtration Rate - Abstract
Podocytes are dynamic polarized cells that lie on the surface of glomerular capillaries and comprise an essential component of the glomerular filtration barrier. Insulin provoked a sustained, approximately 70%, increase in intracellular calcium concentration in podocytes. RT-PCR revealed the presence of mRNA encoding sarco/endoplasmic reticulum calcium ATPase isoforms 1-3, and plasma membrane Ca(2+) pump (PMCA) isoforms 1,3,4; mRNA levels were depressed by the addition of insulin. Inhibitors of PMCA, and the Na(+) -Ca(2+) exchanger, increased podocyte permeability to albumin, induced dimerization of protein kinase G type I alpha (PKGIα), and activation of PKGIα-dependent signaling. These data suggest the involvement of calcium and PKGIα signaling in insulin-enhanced filtration barrier permeability in podocytes.
- Published
- 2016
19. Proximal tubule albumin uptake – potential role for endothelin system in sickle cell disease mice
- Author
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Hasan Alrefai, Malgorzata Kasztan, Crystal M Taylor, and David M. Pollock
- Subjects
medicine.medical_specialty ,Chemistry ,Cell ,Albumin ,Disease ,Biochemistry ,medicine.anatomical_structure ,Endocrinology ,Internal medicine ,Genetics ,medicine ,Proximal tubule ,Endothelin system ,Molecular Biology ,Biotechnology - Published
- 2020
20. Abstract 044: Purinoceptor-Dependent Regulation of Sodium Excretion is Sexually Dimorphic
- Author
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Shali Zhang, Edward W. Inscho, Malgorzata Kasztan, Eman Y. Gohar, and David M. Pollock
- Subjects
medicine.medical_specialty ,Kidney ,business.industry ,medicine.drug_class ,Sodium ,chemistry.chemical_element ,Lower risk ,Sexual dimorphism ,Excretion ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Estrogen ,Sodium excretion ,Internal medicine ,Internal Medicine ,Medicine ,business - Abstract
Premenopausal women have a lower risk of hypertension compared to age-matched men. Recently, prominent roles have been assigned to P2Y 2 and P2Y 4 purinoceptor subtypes in promoting Na + excretion, implicating dysfunction of these receptors as potential contributors to hypertension. We recently reported that activation of P2Y 2 and P2Y 4 receptors in the renal medulla by UTP promotes Na + excretion in male rats. In intact females, UTP did not stimulate Na + excretion while ovariectomy unmasked UTP-induced natriuresis. These observations led us to hypothesize that intact females have higher basal renal medullary activity of P2Y 2 and P2Y 4 receptors in regulating Na + excretion compared to male and ovariectomized (OVX) rats. To test that, we determined (i) P2Y 2 and P2Y 4 mRNA and protein expression in the inner medulla from male, intact female and OVX Sprague Dawley rats and (ii) the effect of inhibiting medullary purinoceptors (P2 receptors) on Na + excretion in those rats. We found that P2Y 2 and P2Y 4 mRNA expression was higher in the inner medulla from females compared to males (1.00±0.09 vs. 0.70±0.05 and 1.00±0.22 vs. 0.29±0.05, respectively, P2 and P2Y 4 mRNA expression were eliminated by ovariectomy (0.60±0.06 and 0.29±0.04, respectively, p2 receptor, compared to males. In anesthetized rats, medullary P2 receptor inhibition by suramin (P2 receptor antagonist, 750 μg/kg/min) significantly attenuated Na + excretion in intact females (0.4±0.1 vs. 0.9±0.2 μmol/min, P2 ) increases the expression of P2Y 2 and P2Y 4 receptors, we subjected cultured mouse inner medullary collecting duct cells (mIMCD3) to different concentrations of E 2 (0, 10, 100 and 1000 nM). We found that E 2 dose-dependently increased the expression of P2Y 2 and P2Y 4 mRNA in mIMCD3. These data suggest that females have enhanced P2Y 2 and P2Y 4 -dependent regulation of Na + excretion in the renal medulla, compared to male and OVX rats, at least partially via an E 2 -dependent mechanism. This pathway may contribute to facilitated renal Na + handling in premenopausal females.
- Published
- 2018
21. Reduced Renal Primary Cilia Expression in Humanized Sickle Cell Mice
- Author
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Malgorzata Kasztan, Jennifer S. Pollock, Crystal M Taylor, Bradley K. Yoder, and David M. Pollock
- Subjects
genetic structures ,business.industry ,media_common.quotation_subject ,Cilium ,Cell ,Longevity ,Disease ,Biochemistry ,eye diseases ,medicine.anatomical_structure ,Immunology ,Genetics ,medicine ,sense organs ,business ,Molecular Biology ,Biotechnology ,media_common - Abstract
Sickle cell disease (SCD) is an autosomal recessive hematologic disorder that afflicts millions of people across the globe. As longevity improves due to therapeutic advancements, end-organ damage, ...
- Published
- 2018
22. α1‐Adrenoreceptor‐Mediated Vasoconstriction is Enhanced in the Aorta but not Resistance Arteries of Humanized Sickle Cell Mice
- Author
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J. Miller Allan, Chunhua Jin, David M. Pollock, Brandon M. Fox, Malgorzata Kasztan, Patrick Axel Molina, Randee S. Sedaka, and Jennifer S. Pollock
- Subjects
Aorta ,business.industry ,Cell ,Pharmacology ,Biochemistry ,medicine.anatomical_structure ,medicine.artery ,Genetics ,medicine ,medicine.symptom ,business ,Molecular Biology ,Vasoconstriction ,Biotechnology - Published
- 2018
23. KIM‐1 as a new biomarker for glomerular hyperfiltration and chronic kidney disease in humanized sickle cell disease mice
- Author
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Joshua S. Speed, Malgorzata Kasztan, David M. Pollock, Tim M. Townes, and Brandon M. Fox
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Cell ,Disease ,urologic and male genital diseases ,medicine.disease ,Biochemistry ,Nephropathy ,medicine.anatomical_structure ,Genetics ,medicine ,Biomarker (medicine) ,business ,Molecular Biology ,Glomerular hyperfiltration ,Biotechnology ,Kidney disease - Abstract
Sickle cell disease is associated with increased prevalence of nephropathy and approximately 30% mortality from chronic kidney disease and renal failure. The spectrum of renal manifestations includ...
- Published
- 2018
24. Interplay between renal endothelin and purinergic signaling systems
- Author
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Malgorzata Kasztan, Eman Y. Gohar, and David M. Pollock
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Physiology ,Natriuresis ,Blood Pressure ,Review ,Biology ,Pharmacology ,03 medical and health sciences ,Adenosine Triphosphate ,Internal medicine ,Extracellular fluid ,medicine ,Animals ,Humans ,Kidney Tubules, Collecting ,Kidney ,Endothelin-1 ,Receptors, Endothelin ,Receptors, Purinergic P2 ,Purinergic receptor ,Sodium, Dietary ,Purinergic signalling ,030104 developmental biology ,Blood pressure ,medicine.anatomical_structure ,Endocrinology ,Hypertension ,Endothelin receptor ,Homeostasis ,Signal Transduction - Abstract
Alterations in extracellular fluid volume regulation and sodium balance may result in the development and maintenance of salt-dependent hypertension, a major risk factor for cardiovascular disease. Numerous pathways contribute to the regulation of sodium excretion and blood pressure, including endothelin and purinergic signaling. Increasing evidence suggests a link between purinergic receptor activation and endothelin production within the renal collecting duct as a means of promoting natriuresis. A better understanding of the relationship between these two systems, especially in regard to sodium homeostasis, will fill a significant knowledge gap and may provide novel antihypertensive treatment options. Therefore, this review focuses on the cross talk between endothelin and purinergic signaling as it relates to the renal regulation of sodium and blood pressure homeostasis.
- Published
- 2016
25. Insulin increases filtration barrier permeability via TRPC6-dependent activation of PKGIα signaling pathways
- Author
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Malgorzata Kasztan, Agnieszka Piwkowska, Dorota Rogacka, Patrycja Rachubik, Michał Rychłowski, Maciej Jankowski, Stefan Angielski, and Irena Audzeyenka
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Biology ,Permeability ,Podocyte ,TRPC6 ,03 medical and health sciences ,Downregulation and upregulation ,Glomerular Filtration Barrier ,Internal medicine ,medicine ,Animals ,Insulin ,Rats, Wistar ,Molecular Biology ,TRPC ,Cyclic GMP-Dependent Protein Kinase Type I ,TRPC Cation Channels ,Imidazoles ,Actin cytoskeleton ,Cell biology ,Rats ,Enzyme Activation ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Molecular Medicine ,Female ,cGMP-dependent protein kinase ,Signal Transduction - Abstract
Podocytes are dynamic polarized cells on the surface of glomerular capillaries and an essential component of the glomerular filtration barrier. Insulin increases the activation of protein kinase G type Iα (PKGIα) subunits, leading to podocyte dysfunction. In addition, accumulating evidence suggests that TRPC6 channels are crucial mediators of podocyte calcium handling and involved in the regulation of glomerular filtration. Therefore, we investigated whether TRPC6 is involved in the regulation of filtration barrier permeability by insulin via the PKGIα-dependent manner. TRPC channel inhibitor SKF96365 abolished insulin-dependent glomerular albumin permeability and transepithelial albumin flux in cultured rat podocytes. Insulin-evoked albumin permeability across podocyte monolayers was also blocked using TRPC6 siRNA. The effect of insulin on albumin permeability was mimicked by treating podocytes with TRPC channel activator (oleolyl-2-acetyl-sn-glycerol, OAG). Insulin or OAG treatment rapidly increased the superoxide generation through activation of NADH oxidase. TRPC inhibitor SKF96365 or siRNA knockdown of TRPC6 attenuated insulin-dependent increase of ROS production. Furthermore, TRPC inhibitor or downregulation of TRPC6 blocked insulin-induced rearrangement of the actin cytoskeleton and attenuated oxidative activation of PKGIα and changes in the phosphorylation of PKG target proteins MYPT1 and MLC. Moreover insulin regulated the PKGIα interaction with TRPC6 in cultured rat podocytes. Taken together, our data suggest a key role of TRPC6 channels in the mediation of insulin-dependent activation of PKGIα signaling pathways. Overall, we have identified a potentially important mechanism that may explain disturbances in filtration barrier permeability in many diseases with increased expression of TRPC6 and chronic Ca2+ overload.
- Published
- 2016
26. Tauroursodeoxycholic acid (TUDCA) abolishes chronic high salt‐induced renal injury and inflammation
- Author
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Andrew Abad, Randee Sedaka, Carmen De Miguel, Jeremie M. Lever, Malgorzata Kasztan, Jennifer S. Pollock, Pamela K. Carmines, Chunhua Jin, Michelle Sonnenberger, and David M. Pollock
- Subjects
Male ,0301 basic medicine ,Programmed cell death ,medicine.medical_specialty ,Brush border ,Physiology ,Renal cortex ,Inflammation ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,Article ,Animals, Genetically Modified ,Taurochenodeoxycholic Acid ,Excretion ,Random Allocation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Sodium Chloride, Dietary ,Proteinuria ,business.industry ,Tauroursodeoxycholic acid ,Receptor, Endothelin B ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Albuminuria ,Kidney Diseases ,medicine.symptom ,business ,Gene Deletion - Abstract
AIM: Chronic high salt intake exaggerates renal injury and inflammation, especially with the loss of functional ET(B) receptors. Tauroursodeoxycholic acid (TUDCA) is a chemical chaperone and bile salt that is approved for the treatment of hepatic diseases. Our aim was to determine whether TUDCA is reno-protective in a model of ET(B) receptor deficiency with chronic high salt-induced renal injury and inflammation. METHODS: ET(B)-deficient and transgenic control rats were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet for 3 weeks, receiving TUDCA (400 mg/kg/day; i.p.) or vehicle. Histological and biochemical markers of kidney injury, renal cell death and renal inflammation were assessed. RESULTS: In ET(B)-deficient rats, high salt diet significantly increased glomerular and proximal tubular histological injury, proteinuria, albuminuria, excretion of tubular injury markers KIM-1 and NGAL, renal cortical cell death and renal CD4(+) T cell numbers. TUDCA treatment increased proximal tubule megalin expression as well as prevented high salt diet-induced glomerular and tubular damage in ET(B)-deficient rats, as indicated by reduced kidney injury markers, decreased glomerular permeability and proximal tubule brush border restoration, as well as reduced renal inflammation. However, TUDCA had no significant effect on blood pressure. CONCLUSIONS: TUDCA protects against the development of glomerular and proximal tubular damage, decreases renal cell death, and inflammation in the renal cortex in rats with ET(B) receptor dysfunction on a chronic high salt diet. These results highlight the potential use of TUDCA as a preventive tool against chronic high salt induced renal damage.
- Published
- 2018
27. Chronic renal denervation increases renal tubular response to P2X receptor agonists in rats: implication for renal sympathetic nerve ablation
- Author
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Maciej Jankowski, Miroslawa Szczepanska-Konkel, Malgorzata Kasztan, Robert Kowalski, and Ewelina Kreft
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Sympathetic Nervous System ,Fractional excretion of sodium ,medicine.drug_class ,Renal function ,P2 receptor ,Kidney ,Natriuresis ,Kidney Tubules, Proximal ,Norepinephrine ,chemistry.chemical_compound ,Adenosine Triphosphate ,Internal medicine ,medicine ,Animals ,Arterial Pressure ,PPADS ,Rats, Wistar ,Denervation ,Transplantation ,business.industry ,Rats ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Receptors, Purinergic P2X ,Nephrology ,Pyridoxal Phosphate ,Sodium-Potassium-Exchanging ATPase ,business - Abstract
BACKGROUND Kidney noradrenergic innervation regulates tubular function. Adenosine triphosphate (ATP)-a co-transmitter of norepinephrine-acts on purinoceptors, including ion channel receptor, P2X. P2X receptor agonists, α,β-methylene ATP (α,β-meATP) and β,γ-methylene ATP (β,γ-meATP), induce natriuresis. Regarding the functional co-localization of adrenoceptors and P2X receptors, we evaluated rat renal tubular system sensitivity to natriuretic action of P2X receptor agonists in chronically denervated kidney. METHODS Clearance studies with α,β-meATP and β,γ-meATP (intravenous infusion rate, 2 µmol/kg + 20 nmol/kg/min) were performed after bilateral surgical kidney denervation (DNx) and sham-operation (Sham). Na/K-ATPase activity was measured in isolated rat renal proximal tubules. RESULTS In DNx compared with Sham, saline infusion significantly increased renal sodium and urine excretion and P2X receptor agonist infusion was significantly more natriuretic and diuretic. In DNx and Sham, respectively, α,β-meATP increased fractional excretion of sodium (FE(Na)) by 2 ± 0.3 and 0.6 ± 0.1% and urine (FE(V)) by 1.6 ± 0.3 and 0.9 ± 0.2%; β,γ-meATP had similar effects. In both groups of rats, natriuretic and diuretic actions were abolished by P2 receptor blocker (pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate, PPADS), mean arterial blood pressure and glomerular filtration rate remained unchanged during infusion of P2X receptor agonists and antagonist and basal Na/K-ATPase activities in isolated proximal tubules were similar. Both α,β-meATP and β,γ-me-ATP decreased the Na/K-ATPase activity, with 20% inhibition (P < 0.05) in denervated and innervated rats; these inhibitory effects were abolished in the presence of PPADS. CONCLUSIONS Decreased renal sympathetic activity enhances the natriuretic effect of P2X receptor stimulation. This effect is probably not related to altered Na/K-ATPase activity in renal proximal tubules.
- Published
- 2012
28. Endothelin-1 and the kidney: new perspectives and recent findings
- Author
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David M. Pollock, Malgorzata Kasztan, Carmen De Miguel, Eman Y. Gohar, and Joshua S. Speed
- Subjects
0301 basic medicine ,Epithelial sodium channel ,Endothelin Receptor Antagonists ,medicine.medical_specialty ,030232 urology & nephrology ,Nephron ,Kidney ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Homeostasis ,Humans ,Sex Characteristics ,Endothelin-1 ,business.industry ,Podocytes ,Sodium ,Endoplasmic Reticulum Stress ,Endothelin 1 ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Nephrology ,Renal physiology ,Glomerular Filtration Barrier ,Kidney Diseases ,business ,Endothelin receptor - Abstract
Purpose of review The role of endothelin-1 (ET-1) in the kidney has been under study for many years; however, the complex mechanisms by which endothelin controls the physiology/pathophysiology of this organ are not fully resolved. This review aims to summarize recent findings in the field, especially regarding glomerular and tubular damage, Na/water homeostasis and sex differences in ET-1 function. Recent findings Podocytes have been recently identified as a target of ET-1 in the glomerular filtration barrier via ETA receptor activation. Activation of the ETA receptor by ET-1 leads to renal tubular damage by promoting endoplasmic reticulum stress and apoptosis in these cells. In addition, high flow rates in the nephron in response to high salt intake induce ET-1 production by the collecting ducts and promote nitric oxide-dependent natriuresis through epithelial sodium channel inhibition. Recent evidence also indicates that sex hormones regulate the renal ET-1 system differently in men and women, with estrogen suppressing renal ET-1 production and testosterone upregulating that production. Summary Based on the reports reviewed in here, targeting of the renal endothelin system is a possible therapeutic approach against the development of glomerular injury. More animal and clinical studies are needed to better understand the dimorphic control of this system by sex hormones.
- Published
- 2015
29. Increased Glomerular ET‐1 in Female Sickle Cell Mice is Abolished by Chronic Hydroxyurea Treatment
- Author
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Joshua S. Speed, Malgorzata Kasztan, and David M. Pollock
- Subjects
medicine.medical_specialty ,medicine.anatomical_structure ,Endocrinology ,business.industry ,Internal medicine ,Cell ,Genetics ,Medicine ,business ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2015
30. Insulin increases glomerular filtration barrier permeability through PKGIα-dependent mobilization of BKCa channels in cultured rat podocytes
- Author
-
Malgorzata Kasztan, Dorota Rogacka, Agnieszka Piwkowska, Irena Audzeyenka, Stefan Angielski, and Maciej Jankowski
- Subjects
Glucose uptake ,Filtration barrier permeability ,Podocyte ,Large-conductance Ca2+-activated K+ channels ,Permeability ,Constriction apparatus ,Glomerular Filtration Barrier ,Albumins ,medicine ,Animals ,Insulin ,Calcium Signaling ,Rats, Wistar ,Large-Conductance Calcium-Activated Potassium Channel alpha Subunits ,Molecular Biology ,Cells, Cultured ,Cyclic GMP-Dependent Protein Kinase Type I ,biology ,Chemistry ,Podocytes ,Glucose transporter ,Iberiotoxin ,Actin cytoskeleton ,Cell biology ,Rats ,Insulin receptor ,Protein Transport ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Molecular Medicine ,Female ,Peptides ,cGMP-dependent protein kinase - Abstract
Podocytes are highly specialized cells that wrap around glomerular capillaries and comprise a key component of the glomerular filtration barrier. They are uniquely sensitive to insulin; like skeletal muscle and fat cells, they exhibit insulin-stimulated glucose uptake and express glucose transporters. Podocyte insulin signaling is mediated by protein kinase G type I (PKGI), and it leads to changes in glomerular permeability to albumin. Here, we investigated whether large-conductance Ca 2 + -activated K + channels (BK Ca ) were involved in insulin-mediated, PKGIα-dependent filtration barrier permeability. Insulin-induced glomerular permeability was measured in glomeruli isolated from Wistar rats. Transepithelial albumin flux was measured in cultured rat podocyte monolayers. Expression of BK Ca subunits was detected by RT-PCR. BK Ca , PKGIα, and upstream protein expression were examined in podocytes with Western blotting and immunofluorescence. The BK Ca –PKGIα interaction was assessed with co-immunoprecipitation. RT-PCR showed that primary cultured rat podocytes expressed mRNAs that encoded the pore-forming α subunit and four accessory β subunits of BK Ca . The BK Ca inhibitor, iberiotoxin (ibTX), abolished insulin-dependent glomerular albumin permeability and PKGI-dependent transepithelial albumin flux. Insulin-evoked albumin permeability across podocyte monolayers was also blocked with BK Ca siRNA. Moreover, ibTX blocked insulin-induced disruption of the actin cytoskeleton and changes in the phosphorylation of PKG target proteins, MYPT1 and RhoA. These results indicated that insulin increased filtration barrier permeability through mobilization of BK Ca channels via PKGI in cultured rat podocytes. This molecular mechanism may explain podocyte injury and proteinuria in diabetes.
- Published
- 2015
31. Insulin increases glomerular filtration barrier permeability through dimerization of protein kinase G type Iα subunits
- Author
-
Agnieszka Piwkowska, Malgorzata Kasztan, Maciej Jankowski, Dorota Rogacka, and Stefan Angielski
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Filtration barrier permeability ,Podocyte ,Permeability ,chemistry.chemical_compound ,Hyperinsulinemia ,Protein kinase G type Iα ,Superoxides ,Internal medicine ,Protein Phosphatase 1 ,medicine ,Animals ,Insulin ,Rats, Wistar ,Molecular Biology ,Cells, Cultured ,Serum Albumin ,Cyclic GMP-Dependent Protein Kinase Type I ,NADPH oxidase ,Membrane Glycoproteins ,biology ,Chemistry ,Superoxide ,Podocytes ,urogenital system ,Albumin ,NAD(P)H oxidase ,NADPH Oxidases ,Actin cytoskeleton ,Rats ,Rats, Zucker ,Actin Cytoskeleton ,medicine.anatomical_structure ,Endocrinology ,NADPH Oxidase 4 ,NADPH Oxidase 2 ,Glomerular Filtration Barrier ,biology.protein ,Molecular Medicine ,Female ,Protein Multimerization ,Glomerular Filtration Rate - Abstract
The increase in the permeability of the glomerular barrier filtration to albumin is a well-known feature of diabetic microvasculature and a negative prognostic factor for vascular complications. However, the underlying mechanisms are incompletely understood. We demonstrated recently that superoxide anion generation increases dimerization of protein kinase G type Iα (PKGIα) subunits, leading to podocyte dysfunction. Here we investigated whether high insulin concentration is involved in PKGI-dependent hyperpermeability of the diabetic glomerular filtration barrier. We assessed changes in insulin-induced glomerular permeability by measuring glomerular capillary permeability to albumin in isolated glomeruli from Wistar and obese and lean Zucker rats and transmembrane albumin flux in cultured rat podocytes. Expression of PKGIα and upstream proteins was confirmed in the podocytes using Western blotting and immunofluorescence. Insulin (300nM, 5min) increased NAD(P)H-dependent glomerular albumin permeability in Wistar rats and PKGI-dependent transmembrane albumin flux in cultured podocytes. Podocyte exposure to insulin in non-reducing conditions increased PKGIα interprotein disulfide bond formation, altered the phosphorylation of the PKG target proteins MYPT1 and MLC, and disrupted the actin cytoskeleton. The role of NADPH oxidase (NOX) in insulin-induced reactive oxygen species (ROS) generation and insulin-evoked increases in albumin permeability in podocytes was confirmed with NOX2 and NOX4 siRNA. Glomerular albumin permeability was increased in hyperinsulinemic Zucker obese rats with isolated glomeruli showing increased expression of PKGIα and NOX4. Taken together, these data demonstrate that insulin increases glomerular barrier albumin permeability via a PKGI-dependent mechanism involving NAD(P)H-dependent generation of superoxide anion. These findings reveal a role for insulin in the pathophysiology of diabetic glomerular nephropathy.
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