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Article ; Online: Histone Deacetylases in Kidney Physiology and Acute Kidney Injury.

Hyndman, Kelly A

2020 Volume 40, Issue 2, Page(s) 138–147

Abstract: Histone deacetylases (HDACs) are part of the epigenetic machinery that regulates transcriptional processes. The current paradigm is that HDACs silence gene expression via regulation of histone protein lysine deacetylation, or by forming corepressor ... ...

Abstract	Histone deacetylases (HDACs) are part of the epigenetic machinery that regulates transcriptional processes. The current paradigm is that HDACs silence gene expression via regulation of histone protein lysine deacetylation, or by forming corepressor complexes with transcription factors. However, HDACs are more than just nuclear proteins, and they can interact and deacetylate a growing number of nonhistone proteins to regulate cellular function. Cancer-field studies have shown that deranged HDAC activity results in uncontrolled proliferation, inflammation, and fibrosis; all pathologies that also may occur in kidney disease. Over the past decade, studies have emerged suggesting that HDAC inhibitors may prevent and potentially treat various models of acute kidney injury. This review focuses on the physiology of kidney HDACs and highlights the recent advances using HDAC inhibitors to potentially treat kidney disease patients.
MeSH term(s)	Acute Kidney Injury/drug therapy ; Acute Kidney Injury/etiology ; Acute Kidney Injury/genetics ; Acute Kidney Injury/prevention & control ; Animals ; Antineoplastic Agents/adverse effects ; Cisplatin/adverse effects ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Histones/metabolism ; Humans ; Kidney/drug effects ; Kidney/metabolism ; Reperfusion Injury/complications ; Sepsis/complications ; Ureteral Obstruction/complications
Chemical Substances	Antineoplastic Agents ; Histone Deacetylase Inhibitors ; Histones ; Histone Deacetylases (EC 3.5.1.98) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2020-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	604652-6
ISSN	1558-4488 ; 0270-9295
ISSN (online)	1558-4488
ISSN	0270-9295
DOI	10.1016/j.semnephrol.2020.01.005
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Article ; Online: The Seventeenth International Conference on Endothelin (ET-17).

Gumz, Michelle L / Hyndman, Kelly A

Canadian journal of physiology and pharmacology

2022

Abstract: The Seventeenth International Conference on Endothelin (ET-17) was held during 4-7 October 2021 and because of the SARS-CoV-2 pandemic it was held virtually. Sponsored by the American Physiological Society, ET-17 was held over 4 half-days, with exciting ... ...

Abstract	The Seventeenth International Conference on Endothelin (ET-17) was held during 4-7 October 2021 and because of the SARS-CoV-2 pandemic it was held virtually. Sponsored by the American Physiological Society, ET-17 was held over 4 half-days, with exciting studies related to all organ systems presented. Since the
Language	English
Publishing date	2022-09-28
Publishing country	Canada
Document type	Journal Article
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/cjpp-2022-0091
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Article ; Online: Mild dehydration effects on the murine kidney single-nucleus transcriptome and chromatin accessibility.

Huynh, Nha Van / Rehage, Cassidy / Hyndman, Kelly A

American journal of physiology. Renal physiology

2023 Volume 325, Issue 6, Page(s) F717–F732

Abstract: Daily, we may experience mild dehydration with a rise in plasma osmolality that triggers the release of vasopressin. Although the effect of dehydration is well characterized in collecting duct principal cells (CDPCs), we hypothesized that mild ... ...

Abstract	Daily, we may experience mild dehydration with a rise in plasma osmolality that triggers the release of vasopressin. Although the effect of dehydration is well characterized in collecting duct principal cells (CDPCs), we hypothesized that mild dehydration (<12 h) results in many kidney cell-specific changes in transcriptomes and chromatin accessibility. Single-nucleus (sn) multiome (RNA-assay for transposase-accessible chromatin) sequencing and bulk RNA sequencing of kidneys from male and female mice that were mildly water deprived or not were compared. Water-deprived mice had a significant increase in plasma osmolality. sn-multiome-seq resulted in 19,837 nuclei that were annotated into 33 clusters. In CDPCs, aquaporin 2 (
MeSH term(s)	Mice ; Animals ; Male ; Female ; Dehydration/metabolism ; Transcriptome ; Chromatin/genetics ; Chromatin/metabolism ; Aquaporin 2/genetics ; Aquaporin 2/metabolism ; Kidney/metabolism ; Water/metabolism
Chemical Substances	Chromatin ; Aquaporin 2 ; Water (059QF0KO0R)
Language	English
Publishing date	2023-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00161.2023
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Article ; Online: Could NAD

Hyndman, Kelly A / Griffin, Matthew D

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 6, Page(s) 1270–1273

MeSH term(s)	Diabetes Mellitus ; Diabetic Nephropathies/prevention & control ; Dietary Supplements ; Humans ; NAD ; Sirtuin 1
Chemical Substances	NAD (0U46U6E8UK) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2021-04-14
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2021020275
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Article ; Online: Kidney cell type-specific changes in the chromatin and transcriptome landscapes following epithelial

Hyndman, Kelly A / Crossman, David K

Physiological genomics

2021 Volume 54, Issue 2, Page(s) 45–57

Abstract: Recent studies have identified at least 20 different kidney cell types based upon chromatin structure and gene expression. Histone deacetylases (HDACs) are epigenetic transcriptional repressors via deacetylation of histone lysines resulting in ... ...

Abstract	Recent studies have identified at least 20 different kidney cell types based upon chromatin structure and gene expression. Histone deacetylases (HDACs) are epigenetic transcriptional repressors via deacetylation of histone lysines resulting in inaccessible chromatin. We reported that kidney epithelial HDAC1 and HDAC2 activity is critical for maintaining a healthy kidney and preventing fluid-electrolyte abnormalities. However, to what extent does
MeSH term(s)	Animals ; Aquaporin 1/genetics ; Aquaporin 1/metabolism ; Aquaporin 2/genetics ; Aquaporin 2/metabolism ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin Immunoprecipitation Sequencing/methods ; Epithelial Cells/metabolism ; Female ; Gene Expression Profiling/methods ; Histone Deacetylase 1/genetics ; Histone Deacetylase 1/metabolism ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Kidney/cytology ; Kidney/metabolism ; Male ; Mice, Knockout ; RNA-Seq/methods ; Transcriptome/genetics ; Mice
Chemical Substances	Aquaporin 2 ; Carrier Proteins ; Chromatin ; TARSH protein, mouse ; Aquaporin 1 (146410-94-8) ; Histone Deacetylase 1 (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98)
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2038823-8
ISSN	1531-2267 ; 1094-8341
ISSN (online)	1531-2267
ISSN	1094-8341
DOI	10.1152/physiolgenomics.00102.2021
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Article ; Online: Introduction: The 2022 Acute Kidney Injury: Bench to Bedside Conference.

Hyndman, Kelly A / Hukriede, Neil / de Caestecker, Mark

Seminars in nephrology

2022 Volume 42, Issue 3, Page(s) 151275

MeSH term(s)	Humans ; Acute Kidney Injury/therapy
Language	English
Publishing date	2022-11-17
Publishing country	United States
Document type	Editorial
ZDB-ID	604652-6
ISSN	1558-4488 ; 0270-9295
ISSN (online)	1558-4488
ISSN	0270-9295
DOI	10.1016/j.semnephrol.2022.10.001
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Article ; Online: Endothelin system expression in the kidney following cisplatin-induced acute kidney injury in male and female mice.

Gales, Anabelle / Monteiro-Pai, Sureena / Hyndman, Kelly A

Canadian journal of physiology and pharmacology

2022 Volume 100, Issue 9, Page(s) 868–879

Abstract: The chemotherapeutic agent cisplatin accumulates in the kidney and induces acute kidney injury (AKI). Preclinical and clinical studies suggest that young female mice and women show greater recovery from cisplatin-AKI compared to young male mice and men. ... ...

Abstract	The chemotherapeutic agent cisplatin accumulates in the kidney and induces acute kidney injury (AKI). Preclinical and clinical studies suggest that young female mice and women show greater recovery from cisplatin-AKI compared to young male mice and men. The endothelin (ET) and ET receptors are enriched in the kidney and may be dysfunctional in cisplatin-AKI; however, there is a gap in our knowledge about the putative effects of sex and cisplatin on the renal ET system. We hypothesized that cisplatin-AKI male and female mice will have increased expression of the renal ET system. As expected, all cisplatin-AKI mice had kidney damage and body weight loss greater than control mice. Cisplatin-AKI mice had greater cortical
MeSH term(s)	Acute Kidney Injury/chemically induced ; Acute Kidney Injury/drug therapy ; Acute Kidney Injury/genetics ; Animals ; Antineoplastic Agents/toxicity ; Apoptosis ; Cisplatin/toxicity ; Endothelin-1/metabolism ; Female ; Kidney ; Male ; Mice ; Mice, Inbred C57BL
Chemical Substances	Antineoplastic Agents ; Endothelin-1 ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-06-15
Publishing country	Canada
Document type	Journal Article
ZDB-ID	127527-6
ISSN	1205-7541 ; 0008-4212
ISSN (online)	1205-7541
ISSN	0008-4212
DOI	10.1139/cjpp-2022-0126
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Article ; Online: The contribution of collecting duct NOS1 to the concentrating mechanisms in male and female mice.

Mendoza, Luciano D / Hyndman, Kelly A

American journal of physiology. Renal physiology

2019 Volume 317, Issue 3, Page(s) F547–F559

Abstract: The collecting duct (CD) concentrates the urine, thereby maintaining body water volume and plasma osmolality within a normal range. The endocrine hormone arginine vasopressin acts in the CD to increase water permeability via the vasopressin 2 receptor ( ... ...

Abstract	The collecting duct (CD) concentrates the urine, thereby maintaining body water volume and plasma osmolality within a normal range. The endocrine hormone arginine vasopressin acts in the CD to increase water permeability via the vasopressin 2 receptor (V2R)-aquaporin (AQP) axis. Recent studies have suggested that autocrine factors may also contribute to the regulation of CD water permeability. Nitric oxide is produced predominantly by nitric oxide synthase 1 (NOS1) in the CD and acts as a diuretic during salt loading. The present study sought to determine whether CD NOS1 regulates diuresis during changes in hydration status. Male and female control and CD NOS1 knockout (CDNOS1KO) mice were hydrated (5% sucrose water), water deprived, or acutely challenged with the V2R agonist desmopressin. In male mice, water deprivation resulted in decreased urine flow and increased plasma osmolality, copeptin concentration, and kidney AQP2 abundance independent of CD NOS1. In female control mice, water deprivation reduced urine flow, increased plasma osmolality and copeptin, but did not significantly change total AQP2; however, there was increased basolateral AQP3 localization. Surprisingly, female CDNOS1KO mice while on the sucrose water presented with symptoms of dehydration. Fibroblast growth factor 21, an endocrine regulator of sweetness preference, was significantly higher in female CDNOS1KO mice, suggesting that this was reducing their drive to drink the sucrose water. With acute desmopressin challenge, female CDNOS1KO mice failed to appropriately concentrate their urine, resulting in higher plasma osmolality than controls. In conclusion, CD NOS1 plays only a minor role in urine-concentrating mechanisms.
MeSH term(s)	Animals ; Antidiuretic Agents/pharmacology ; Aquaporin 2/genetics ; Aquaporin 2/metabolism ; Aquaporin 3/genetics ; Aquaporin 3/metabolism ; Deamino Arginine Vasopressin/pharmacology ; Dehydration/enzymology ; Dehydration/physiopathology ; Disease Models, Animal ; Diuresis/drug effects ; Female ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Kidney Concentrating Ability/drug effects ; Kidney Tubules, Collecting/drug effects ; Kidney Tubules, Collecting/enzymology ; Male ; Mice, Knockout ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/deficiency ; Nitric Oxide Synthase Type I/genetics ; Nitric Oxide Synthase Type I/metabolism ; Organism Hydration Status ; Osmolar Concentration ; Sex Factors ; Signal Transduction ; Urodynamics ; Water Deprivation
Chemical Substances	Antidiuretic Agents ; Aqp2 protein, mouse ; Aqp3 protein, mouse ; Aquaporin 2 ; fibroblast growth factor 21 ; Aquaporin 3 (158801-98-0) ; Nitric Oxide (31C4KY9ESH) ; Fibroblast Growth Factors (62031-54-3) ; Nitric Oxide Synthase Type I (EC 1.14.13.39) ; Nos1 protein, mouse (EC 1.14.13.39) ; Deamino Arginine Vasopressin (ENR1LLB0FP)
Language	English
Publishing date	2019-06-26
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00180.2019
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Article ; Online: Dynamic regulation of lysine acetylation: the balance between acetyltransferase and deacetylase activities.

Hyndman, Kelly A / Knepper, Mark A

American journal of physiology. Renal physiology

2017 Volume 313, Issue 4, Page(s) F842–F846

Abstract: Reversible posttranslational modification of proteins is a critically important process in physiological regulation in all tissues, including the kidney. Lysine acetylation occurs in all organisms, including prokaryotes, and is regulated by a balance ... ...

Abstract	Reversible posttranslational modification of proteins is a critically important process in physiological regulation in all tissues, including the kidney. Lysine acetylation occurs in all organisms, including prokaryotes, and is regulated by a balance between the lysine acetyltransferases (adding an acetyl group to the ε-amino group of a lysine) and deacetylases (removing it). The kidney is an organ rich with acetylated lysines, which map to >2,000 unique histone and nonhistone proteins. However, the functional significance of these modifications remains to be discovered. Here, we have compiled gene lists of the acetyltransferases and deacetylases in the mammalian genomes and mapped their mRNA expression along the renal tubule. These lists will be useful for generating targeted approaches to test the physiological or pathophysiological significance of lysine acetylation changes in the kidney.
MeSH term(s)	Acetylation ; Acetyltransferases/genetics ; Acetyltransferases/metabolism ; Animals ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Nephrons/enzymology
Chemical Substances	Acetyltransferases (EC 2.3.1.-) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2017-07-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00313.2017
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Article ; Online: Physiologic homeostasis after pig-to-human kidney xenotransplantation.

Judd, Eric / Kumar, Vineeta / Porrett, Paige M / Hyndman, Kelly A / Anderson, Douglas J / Jones-Carr, Maggie E / Shunk, Andrew / Epstein, Daniel R / Fatima, Huma / Katsurada, Akemi / Satou, Ryousuke / Navar, L Gabriel / Locke, Jayme E

Kidney international

2024 Volume 105, Issue 5, Page(s) 971–979

Abstract: Demand for kidney grafts outpaces supply, limiting kidney transplantation as a treatment for kidney failure. Xenotransplantation has the potential to make kidney transplantation available to many more patients with kidney failure, but the ability of ... ...

Abstract	Demand for kidney grafts outpaces supply, limiting kidney transplantation as a treatment for kidney failure. Xenotransplantation has the potential to make kidney transplantation available to many more patients with kidney failure, but the ability of xenografts to support human physiologic homeostasis has not been established. A brain-dead adult decedent underwent bilateral native nephrectomies followed by 10 gene-edited (four gene knockouts, six human transgenes) pig-to-human xenotransplantation. Physiologic parameters and laboratory values were measured for seven days in a critical care setting. Data collection aimed to assess homeostasis by measuring components of the renin-angiotensin-aldosterone system, parathyroid hormone signaling, glomerular filtration rate, and markers of salt and water balance. Mean arterial blood pressure was maintained above 60 mmHg throughout. Pig kidneys secreted renin (post-operative day three to seven mean and standard deviation: 47.3 ± 9 pg/mL). Aldosterone and angiotensin II levels were present (post-operative day three to seven, 57.0 ± 8 pg/mL and 5.4 ± 4.3 pg/mL, respectively) despite plasma renin activity under 0.6 ng/mL/hr. Parathyroid hormone levels followed ionized calcium. Urine output down trended from 37 L to 6 L per day with 4.5 L of electrolyte free water loss on post-operative day six. Aquaporin 2 channels were detected in the apical surface of principal cells, supporting pig kidney response to human vasopressin. Serum creatinine down trended to 0.9 mg/dL by day seven. Glomerular filtration rate ranged 90-240 mL/min by creatinine clearance and single-dose inulin clearance. Thus, in a human decedent model, xenotransplantation of 10 gene-edited pig kidneys provided physiologic balance for seven days. Hence, our in-human study paves the way for future clinical study of pig-to-human kidney xenotransplantation in living persons.
MeSH term(s)	Adult ; Humans ; Animals ; Swine ; Renin ; Transplantation, Heterologous ; Kidney/physiology ; Renin-Angiotensin System ; Aldosterone ; Homeostasis ; Renal Insufficiency ; Parathyroid Hormone ; Water
Chemical Substances	Renin (EC 3.4.23.15) ; Aldosterone (4964P6T9RB) ; Parathyroid Hormone ; Water (059QF0KO0R)
Language	English
Publishing date	2024-01-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2024.01.016
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