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Article ; Online: Differences of Uric Acid Transporters Carrying Extracellular Vesicles in the Urine from Uric Acid and Calcium Stone Formers and Non-Stone Formers.

Lin, Zhijian / Jayachandran, Muthuvel / Haskic, Zejfa / Kumar, Sanjay / Lieske, John C

International journal of molecular sciences

2022 Volume 23, Issue 17

Abstract: Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these ... ...

Abstract	Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these EVs may be a pathogenic biomarker of UASD. Methods: Urinary EVs bearing UA transporters (SLC2A9, SLC17A3, SLC22A12, SLC5A8, ABCG2, and ZNF365) were quantified in urine from UA stone formers (UASFs), calcium stone formers (CSFs), and age-/sex-matched non-stone formers (NSFs) using a standardized and published method of digital flow cytometry. Results: Urinary pH was lower (p < 0.05) and serum and urinary UA were greater (p < 0.05) in UASFs compared with NSFs. Urinary EVs carrying SLC17A3 and SLC5A8 were lower (p < 0.05) in UASFs compared with NSFs. Urinary EVs bearing SLC2A9, SLC22A12, SLC5A8, ABCG2, and ZNF365 were lower (p < 0.05) in CSFs than UASFs, while excretion of SLC17A3-bearing EVs did not differ between groups. Conclusion: EVs bearing specific UA transporters might contribute to the pathogenesis of UASD and represent non-invasive pathogenic biomarkers for calcium and UA stone risk.
MeSH term(s)	Calcium ; Calcium Oxalate ; Extracellular Vesicles ; Glucose Transport Proteins, Facilitative ; Humans ; Kidney Calculi/etiology ; Monocarboxylic Acid Transporters ; Organic Anion Transporters/genetics ; Organic Cation Transport Proteins ; Uric Acid
Chemical Substances	Glucose Transport Proteins, Facilitative ; Monocarboxylic Acid Transporters ; Organic Anion Transporters ; Organic Cation Transport Proteins ; SLC22A12 protein, human ; SLC2A9 protein, human ; SLC5A8 protein, human ; Calcium Oxalate (2612HC57YE) ; Uric Acid (268B43MJ25) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-09-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms231710010
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Article ; Online: Preeclampsia and the Kidney: Pathophysiology and Clinical Implications.

Dines, Virginia / Suvakov, Sonja / Kattah, Andrea / Vermunt, Jane / Narang, Kavita / Jayachandran, Muthuvel / Abou Hassan, Coline / Norby, Alexander M / Garovic, Vesna D

Comprehensive Physiology

2023 Volume 13, Issue 1, Page(s) 4231–4267

Abstract: Preeclampsia and other hypertensive disorders of pregnancy are major contributors to maternal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on ... ...

Abstract	Preeclampsia and other hypertensive disorders of pregnancy are major contributors to maternal morbidity and mortality worldwide. This group of disorders includes chronic hypertension, gestational hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension, and eclampsia. The body undergoes important physiological changes during pregnancy to allow for normal placental and fetal development. Several mechanisms have been proposed that may lead to preeclampsia, including abnormal placentation and placental hypoxia, impaired angiogenesis, excessive pro-inflammatory response, immune system imbalance, abnormalities of cellular senescence, alterations in regulation and activity of angiotensin II, and oxidative stress, ultimately resulting in upregulation of multiple mediators of endothelial cell dysfunction leading to maternal disease. The clinical implications of preeclampsia are significant as there are important short-term and long-term health consequences for those affected. Preeclampsia leads to increased risk of preterm delivery and increased morbidity and mortality of both the developing fetus and mother. Preeclampsia also commonly leads to acute kidney injury, and women who experience preeclampsia or another hypertensive disorder of pregnancy are at increased lifetime risk of chronic kidney disease and cardiovascular disease. An understanding of normal pregnancy physiology and the pathophysiology of preeclampsia is essential to develop novel treatment approaches and manage patients with preeclampsia and hypertensive disorders of pregnancy. © 2023 American Physiological Society. Compr Physiol 13:4231-4267, 2023.
MeSH term(s)	Infant, Newborn ; Female ; Pregnancy ; Humans ; Pre-Eclampsia/drug therapy ; Hypertension, Pregnancy-Induced ; Placenta/blood supply ; Kidney ; Cardiovascular Diseases ; Vascular Diseases
Language	English
Publishing date	2023-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c210051
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Article ; Online: Women With a History of Preeclampsia Exhibit Accelerated Aging and Unfavorable Profiles of Senescence Markers.

Suvakov, Sonja / Vaughan, Lisa E / Parashuram, Santosh / Butler Tobah, Yvonne S / Jayachandran, Muthuvel / Kattah, Andrea / Chamberlain, Alanna M / Bielinski, Suzette J / Milic, Natasa / Garovic, Vesna D

Hypertension (Dallas, Tex. : 1979)

2024

Abstract: Background: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, ...

Abstract	Background: Senescence, a mechanism of cellular aging, which is characterized by irreversible proliferation arrest and a proinflammatory secretory phenotype, has been documented in women with preeclampsia. As cellular senescence can persist and progress, we postulated that it is associated with accelerated aging phenotype and accumulation of comorbidities in women with a history of preeclampsia. Methods: We included a cohort of women with a history of preeclampsia (n=40) age- and parity-matched to a group of referent women with normotensive pregnancies (n=40). Women with prior major cardiovascular events, neurological, or autoimmune conditions were excluded. We collected urine and blood samples to study markers of aging, data on multimorbidity at the time of enrollment, and prospectively followed them for events over the course of 6 years, on average. Results: Women with a history of preeclampsia exhibited unfavorable aging profiles compared with referent women, including decreased urinary α-Klotho ( Conclusions: Our data suggest that a history of preeclampsia is associated with accelerated aging as indicated by senescence marker differences and the accumulation of multimorbidity later in life. Targeting cellular senescence may offer novel, mechanism-based approaches for the diagnosis and treatment of adverse health outcomes in women with a history of preeclampsia.
Language	English
Publishing date	2024-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	423736-5
ISSN	1524-4563 ; 0194-911X ; 0362-4323
ISSN (online)	1524-4563
ISSN	0194-911X ; 0362-4323
DOI	10.1161/HYPERTENSIONAHA.123.22250
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Article ; Online: Differences of Uric Acid Transporters Carrying Extracellular Vesicles in the Urine from Uric Acid and Calcium Stone Formers and Non-Stone Formers

Zhijian Lin / Muthuvel Jayachandran / Zejfa Haskic / Sanjay Kumar / John C. Lieske

International Journal of Molecular Sciences, Vol 23, Iss 10010, p

2022 Volume 10010

Abstract	Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these EVs may be a pathogenic biomarker of UASD. Methods: Urinary EVs bearing UA transporters (SLC2A9, SLC17A3, SLC22A12, SLC5A8, ABCG2, and ZNF365) were quantified in urine from UA stone formers (UASFs), calcium stone formers (CSFs), and age-/sex-matched non-stone formers (NSFs) using a standardized and published method of digital flow cytometry. Results: Urinary pH was lower ( p < 0.05) and serum and urinary UA were greater ( p < 0.05) in UASFs compared with NSFs. Urinary EVs carrying SLC17A3 and SLC5A8 were lower ( p < 0.05) in UASFs compared with NSFs. Urinary EVs bearing SLC2A9, SLC22A12, SLC5A8, ABCG2, and ZNF365 were lower ( p < 0.05) in CSFs than UASFs, while excretion of SLC17A3-bearing EVs did not differ between groups. Conclusion: EVs bearing specific UA transporters might contribute to the pathogenesis of UASD and represent non-invasive pathogenic biomarkers for calcium and UA stone risk.
Keywords	urine pH ; urinary vesicles ; renal epithelial cells ; nephrolithiasis ; aciduria ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2022-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli.

Hunter, Larry W / Jayachandran, Muthuvel / Miller, Virginia M

Biology of sex differences

2019 Volume 10, Issue 1, Page(s) 26

Abstract: Background: There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated ... ...

Abstract	Background: There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated by inflammatory and thrombotic factors have the potential to disrupt endothelial cells of the brain microvasculature. Therefore, experiments were designed to identify sex differences in the phenotype of MV released from cultured human brain microvascular endothelial cells (HBMEC) in response to inflammatory and thrombotic stimuli. Methods: Cultured HBMEC derived from 20- to 30-year-old male and female donors were treated for 20 h with medium supplemented with tumor necrosis factor alpha (TNFα; 20 ng/ml), thrombin (THR; 2 U/ml), or vehicle (i.e., control). MV were isolated from the conditioned media by high-speed centrifugation and quantified by digital flow cytometry by labeling with fluorophore-conjugated primary antibodies against PECAM-1, integrin αvβ3, ICAM-1, E-selectin, or MCAM. In addition, temporal uptake of labeled MV into control HBMEC was examined by confocal microscopy. Results: Under control conditions, male HBMEC released fewer MV expressing each antigen, except for PECAM-1, than female cells (P < 0.05). Neither TNFα nor THR reduced cell viability. However, TNFα induced apoptosis in female and male cells, whereas THR increased apoptosis marginally only in male cells. TNFα increased expression of all antigens tested on MV in male cells, but only increased expression of integrin αvβ3, ICAM-1, and E-selectin on MV from female cells. THR increased expression of PECAM-1, ICAM-1, and MCAM-1 on MV from male but not female cells. MV were internalized and localized to lysosomes within 90 min after their application to HBMEC. Conclusions: There are sex differences in expression of cell adhesion molecules on MV released from HBMEC under control conditions and upon activation by TNFα or THR. MV taken up by unstimulated HBMEC may impact the integrity of the brain microvasculature and account, in part, for sex differences in vascular pathologies in the brain.
MeSH term(s)	Adult ; Brain/cytology ; Cell Adhesion Molecules/metabolism ; Cell Survival/drug effects ; Cell-Derived Microparticles/drug effects ; Cell-Derived Microparticles/metabolism ; Cells, Cultured ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Female ; Humans ; Inflammation ; Male ; Microvessels ; Sex Characteristics ; Thrombin/pharmacology ; Thrombosis ; Tumor Necrosis Factor-alpha/pharmacology ; Young Adult
Chemical Substances	Cell Adhesion Molecules ; Tumor Necrosis Factor-alpha ; Thrombin (EC 3.4.21.5)
Language	English
Publishing date	2019-05-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2587352-0
ISSN	2042-6410 ; 2042-6410
ISSN (online)	2042-6410
ISSN	2042-6410
DOI	10.1186/s13293-019-0241-y
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Article ; Online: Impact of Aging and Cellular Senescence in the Pathophysiology of Preeclampsia.

Suvakov, Sonja / Kattah, Andrea G / Gojkovic, Tamara / Enninga, Elizabeth A L / Pruett, Jacob / Jayachandran, Muthuvel / Sousa, Ciria / Santos, Janelle / Abou Hassan, Coline / Gonzales-Suarez, Maria / Garovic, Vesna D

Comprehensive Physiology

2023 Volume 13, Issue 4, Page(s) 5077–5114

Abstract: The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive ... ...

Abstract	The incidence of hypertensive disorders of pregnancy is increasing, which may be due to several factors, including an increased age at pregnancy and more comorbid health conditions during reproductive years. Preeclampsia, the most severe hypertensive disorder of pregnancy, has been associated with an increased risk of future disease, including cardiovascular and kidney diseases. Cellular senescence, the process of cell cycle arrest in response to many physiologic and maladaptive stimuli, may play an important role in the pathogenesis of preeclampsia and provide a mechanistic link to future disease. In this article, we will discuss the pathophysiology of preeclampsia, the many mechanisms of cellular senescence, evidence for the involvement of senescence in the development of preeclampsia, as well as evidence that cellular senescence may link preeclampsia to the risk of future disease. Lastly, we will explore how a better understanding of the role of cellular senescence in preeclampsia may lead to therapeutic trials. © 2023 American Physiological Society. Compr Physiol 13:5077-5114, 2023.
MeSH term(s)	Female ; Humans ; Pregnancy ; Aging/physiology ; Cellular Senescence/physiology ; Pre-Eclampsia/epidemiology ; Pre-Eclampsia/metabolism ; Pre-Eclampsia/physiopathology
Language	English
Publishing date	2023-09-28
Publishing country	United States
Document type	Journal Article
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c230003
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Article ; Online: Correction to: Specific populations of urinary extracellular vesicles and proteins differentiate type 1 primary hyperoxaluria patients without and with nephrocalcinosis or kidney stones.

Jayachandran, Muthuvel / Yuzhakov, Stanislav V / Kumar, Sanjay / Larson, Nicholas B / Enders, Felicity T / Milliner, Dawn S / Rule, Andrew D / Lieske, John C

Orphanet journal of rare diseases

2021 Volume 16, Issue 1, Page(s) 91

Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Published Erratum
ISSN	1750-1172
ISSN (online)	1750-1172
DOI	10.1186/s13023-020-01671-7
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Article ; Online: Sex differences in the expression of cell adhesion molecules on microvesicles derived from cultured human brain microvascular endothelial cells treated with inflammatory and thrombotic stimuli

Larry W. Hunter / Muthuvel Jayachandran / Virginia M. Miller

Biology of Sex Differences, Vol 10, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract Background There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells ... ...

Abstract	Abstract Background There are sex differences in risk for stroke and small vessel ischemic disease in the brain. Microvesicles (MV) derived from activated cells vary by cell of origin and the stimulus initiating their release. MV released from cells activated by inflammatory and thrombotic factors have the potential to disrupt endothelial cells of the brain microvasculature. Therefore, experiments were designed to identify sex differences in the phenotype of MV released from cultured human brain microvascular endothelial cells (HBMEC) in response to inflammatory and thrombotic stimuli. Methods Cultured HBMEC derived from 20- to 30-year-old male and female donors were treated for 20 h with medium supplemented with tumor necrosis factor alpha (TNFα; 20 ng/ml), thrombin (THR; 2 U/ml), or vehicle (i.e., control). MV were isolated from the conditioned media by high-speed centrifugation and quantified by digital flow cytometry by labeling with fluorophore-conjugated primary antibodies against PECAM-1, integrin αvβ3, ICAM-1, E-selectin, or MCAM. In addition, temporal uptake of labeled MV into control HBMEC was examined by confocal microscopy. Results Under control conditions, male HBMEC released fewer MV expressing each antigen, except for PECAM-1, than female cells (P < 0.05). Neither TNFα nor THR reduced cell viability. However, TNFα induced apoptosis in female and male cells, whereas THR increased apoptosis marginally only in male cells. TNFα increased expression of all antigens tested on MV in male cells, but only increased expression of integrin αvβ3, ICAM-1, and E-selectin on MV from female cells. THR increased expression of PECAM-1, ICAM-1, and MCAM-1 on MV from male but not female cells. MV were internalized and localized to lysosomes within 90 min after their application to HBMEC. Conclusions There are sex differences in expression of cell adhesion molecules on MV released from HBMEC under control conditions and upon activation by TNFα or THR. MV taken up by unstimulated HBMEC may impact the integrity of ...
Keywords	Cerebrovascular ; Blood-brain barrier ; Cell adhesion molecules ; Extracellular vesicles ; Sex differences ; Medicine ; R ; Physiology ; QP1-981
Subject code	610
Language	English
Publishing date	2019-05-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: Menopausal hormone therapy, blood thrombogenicity, and development of white matter hyperintensities in women of the Kronos Early Estrogen Prevention Study.

Jayachandran, Muthuvel / Lahr, Brian D / Bailey, Kent R / Miller, Virginia M / Kantarci, Kejal

Menopause (New York, N.Y.)

2020 Volume 27, Issue 3, Page(s) 305–310

Abstract: Objective: Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association.: Methods: ...

Abstract	Objective: Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Methods: Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. Results: WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). Conclusion: In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.
MeSH term(s)	Administration, Cutaneous ; Administration, Oral ; Blood Platelets/pathology ; Brain/diagnostic imaging ; Brain/pathology ; Cell-Derived Microparticles/pathology ; Estradiol/administration & dosage ; Estradiol/adverse effects ; Estrogen Replacement Therapy/adverse effects ; Estrogen Replacement Therapy/methods ; Estrogens/administration & dosage ; Estrogens/adverse effects ; Estrogens, Conjugated (USP)/administration & dosage ; Estrogens, Conjugated (USP)/adverse effects ; Female ; Humans ; Intracranial Thrombosis/chemically induced ; Magnetic Resonance Imaging ; Menopause/blood ; Middle Aged ; Progesterone/administration & dosage ; Progesterone/adverse effects ; White Matter/diagnostic imaging ; White Matter/pathology
Chemical Substances	Estrogens ; Estrogens, Conjugated (USP) ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E)
Language	English
Publishing date	2020-01-28
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1205262-0
ISSN	1530-0374 ; 1072-3714
ISSN (online)	1530-0374
ISSN	1072-3714
DOI	10.1097/GME.0000000000001465
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Zs.A 4111: Show issues

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Article ; Online: Inflammatory Cells in Nephrectomy Tissue from Patients without and with a History of Urinary Stone Disease.

Dejban, Pegah / Wilson, Elena M / Jayachandran, Muthuvel / Herrera Hernandez, Loren P / Haskic, Zejfa / Wellik, Linda E / Sinha, Sutapa / Rule, Andrew D / Denic, Aleksandar / Koo, Kevin / Potretzke, Aaron M / Lieske, John C

Clinical journal of the American Society of Nephrology : CJASN

2022 Volume 17, Issue 3, Page(s) 414–422

Abstract: Background and objectives: Urinary stone disease has been associated with inflammation, but the specific cell interactions that mediate events remain poorly defined. This study compared calcification and inflammatory cell patterns in kidney tissue from ... ...

Abstract	Background and objectives: Urinary stone disease has been associated with inflammation, but the specific cell interactions that mediate events remain poorly defined. This study compared calcification and inflammatory cell patterns in kidney tissue from radical nephrectomy specimens of patients without and with a history of urinary stone disease. Design, setting, participants, & measurements: Nontumor parenchyma of biobanked radical nephrectomy specimens from age- and sex-matched stone formers ( Results: Calcification in the medulla of stone formers was higher than in nonstone formers ( Conclusions: Higher medullary calcification stimulated accumulation of proinflammatory rather than anti-inflammatory macrophages in stone formers.
MeSH term(s)	Female ; Humans ; Kidney Calculi/complications ; Kidney Calculi/surgery ; Male ; Nephrectomy/adverse effects ; Urinary Calculi
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2226665-3
ISSN	1555-905X ; 1555-9041
ISSN (online)	1555-905X
ISSN	1555-9041
DOI	10.2215/CJN.11730921
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