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Article ; Online: Maurice B. Burg (1931-2022), discoverer of kidney transport mechanisms.

Knepper, Mark A

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 30, Page(s) e2209749119

MeSH term(s)	History, 20th Century ; History, 21st Century ; Kidney/physiology ; Nephrology/history ; United States
Language	English
Publishing date	2022-07-15
Publishing country	United States
Document type	Biography ; Historical Article ; Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2209749119
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Article ; Online: Navigating the Omics Frontier: Challenges, Opportunities, and the Future of Precision Nephrology.

Rinschen, Markus M / Knepper, Mark A

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 12, Page(s) 1943–1944

MeSH term(s)	Nephrology ; Genomics ; Proteomics ; Forecasting
Language	English
Publishing date	2023-10-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000255
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Article ; Online: Multiomics Analyses Reveal Sex Differences in Mouse Renal Proximal Subsegments.

Chen, Lihe / Chou, Chung-Lin / Yang, Chin-Rang / Knepper, Mark A

Journal of the American Society of Nephrology : JASN

2023 Volume 34, Issue 5, Page(s) 829–845

Abstract: Significance statement: Sex-dependent differences in kidney function are recognized but the underlying molecular mechanisms are largely unexplored. Advances in genomics and proteomic technologies now allow extensive characterization of differences ... ...

Abstract	Significance statement: Sex-dependent differences in kidney function are recognized but the underlying molecular mechanisms are largely unexplored. Advances in genomics and proteomic technologies now allow extensive characterization of differences between the same cell types of males and females. Multiomics integrating RNA-seq, ATAC-seq, and proteomics data to investigate differences in gene expression, chromatin accessibility, and protein expression in proximal tubules of male and female mice identified many sex-biased genes and proteins associated with kidney functions, including metabolic and transport processes. Sex differences may also arise from variations of the interaction between transcription factors and accessible chromatin regions. A comprehensive web resource is provided to advance understanding of sex differences in cells of the proximal tubule. Background: Sex differences have been increasingly recognized as important in kidney physiology and pathophysiology, but limited resources are available for comprehensive interrogation of sex differences. Methods: RNA-seq and ATAC-seq of microdissected mouse proximal tubules and protein mass spectrometry of homogenized perfused mouse kidneys reveal differences in proximal tubule cells of males and females. Results: The transcriptomic data indicated that the major differences in the proximal tubules between the sexes were in the S2/S3 segments, and most of the sex-biased transcripts mapped to autosomes rather than to the sex chromosomes. Many of the transcripts exhibiting sex-biased expression are involved in monocarboxylic acid metabolic processes, organic anion transport, and organic acid transport. The ATAC-seq method on microdissected tubules captured chromatin accessibility. Many of the more than 7000 differentially accessible DNA regions identified were in distal regions. Motif analyses revealed a lack of direct involvement of estrogen receptors or the androgen receptor (absence of canonical hormone response elements), suggesting an indirect regulatory role of sex hormones. Instead, analyses identified several transcription factors (TFs) ( Tead1 , Nfia/b , and Pou3f3 ) whose interplay with proximal tubule-specific TFs ( e.g. , Hnf1b , Hnf4a ) may contribute to sex differences. Finally, the whole-kidney proteome was correlated with the transcriptome, and many sex-biased proteins ( e.g. , Cyp2e1, Acsm2/3) were identified. Conclusions: Sex-dependent cis-regulatory elements interact with TFs in ways that lead to sex-biased gene expression in proximal tubule cells. These data are provided as a user-friendly web page at https://esbl.nhlbi.nih.gov/MRECA/PT/ .
MeSH term(s)	Mice ; Female ; Male ; Animals ; Sex Characteristics ; Proteomics ; Multiomics ; Kidney/metabolism ; Kidney Tubules, Proximal/metabolism ; Transcription Factors/metabolism ; Chromatin/metabolism
Chemical Substances	Transcription Factors ; Chromatin
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.0000000000000089
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Article ; Online: Prioritizing Functional Goals as We Rebuild the Kidney.

Humphreys, Benjamin D / Knepper, Mark A

Journal of the American Society of Nephrology : JASN

2019 Volume 30, Issue 12, Page(s) 2287–2288

MeSH term(s)	Animals ; Goals ; Kidney ; Mice ; Regeneration ; Stem Cells ; Transplants
Language	English
Publishing date	2019-11-01
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.2019101051
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Article ; Online: Using CRISPR-Cas9/phosphoproteomics to identify substrates of calcium/calmodulin-dependent kinase 2δ.

Park, Euijung / Yang, Chin-Rang / Raghuram, Viswanathan / Chen, Lihe / Chou, Chung-Lin / Knepper, Mark A

The Journal of biological chemistry

2023 Volume 299, Issue 12, Page(s) 105371

Abstract: ... ...

Abstract	Ca
MeSH term(s)	Aquaporin 2/genetics ; Aquaporin 2/metabolism ; Chromatography, Liquid ; CRISPR-Cas Systems ; Kidney Tubules, Collecting/cytology ; Kidney Tubules, Collecting/metabolism ; Phosphorylation ; Tandem Mass Spectrometry ; Proteomics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Gene Deletion ; RNA-Seq ; Computational Biology ; Amino Acid Motifs ; Down-Regulation ; In Vitro Techniques
Chemical Substances	Aquaporin 2 ; Camk2d protein, mouse (EC 2.7.11.17) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
Language	English
Publishing date	2023-10-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105371
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Article ; Online: 'Aquaporin-omics': mechanisms of aquaporin-2 loss in polyuric disorders.

Mak, Angela / Sung, Chih-Chien / Pisitkun, Trairak / Khositseth, Sookkasem / Knepper, Mark A

The Journal of physiology

2023

Abstract: Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin-2 (AQP2) from collecting duct principal cells, explaining the associated ... ...

Abstract	Animal models of a variety of acquired nephrogenic diabetes insipidus (NDI) disorders have identified a common feature: all such models are associated with the loss of aquaporin-2 (AQP2) from collecting duct principal cells, explaining the associated polyuria. To discover mechanisms of AQP2 loss, previous investigators have carried out either transcriptomics (lithium-induced NDI, unilateral ureteral obstruction, endotoxin-induced NDI) or proteomics (hypokalaemia-associated NDI, hypercalcaemia-associated NDI, bilateral ureteral obstruction), yielding contrasting views. Here, to address whether there may be common mechanisms underlying loss of AQP2 in acquired NDI disorders, we have used bioinformatic data integration techniques to combine information from all transcriptomic and proteomic data sets. The analysis reveals roles for autophagy/apoptosis, oxidative stress and inflammatory signalling as key elements of the mechanism that results in loss of AQP2. These processes can cause AQP2 loss through the combined effects of repression of Aqp2 gene transcription, generalized translational repression, and increased autophagic degradation of proteins including AQP2. Two possible types of stress-sensor proteins, namely death receptors and stress-sensitive protein kinases of the EIF2AK family, are discussed as potential triggers for signalling processes that result in loss of AQP2. KEY POINTS: Prior studies have shown in a variety of animal models of acquired nephrogenic diabetes insipidus (NDI) that loss of the aquaporin-2 (AQP2) protein is a common feature. Investigations of acquired NDI using transcriptomics (RNA-seq) and proteomics (protein mass spectrometry) have led to differing conclusions regarding mechanisms of AQP2 loss. Bioinformatic integration of transcriptomic and proteomic data from these prior studies now reveals that acquired NDI models map to three core processes: oxidative stress, apoptosis/autophagy and inflammatory signalling. These processes cause loss of AQP2 through translational repression, accelerated degradation of proteins, and transcriptional repression.
Language	English
Publishing date	2023-04-27
Publishing country	England
Document type	Journal Article
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP284634
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Article ; Online: Collecting duct water permeability inhibition by EGF is associated with decreased cAMP, PKA activity, and AQP2 phosphorylation at Ser

Chou, Chung-Lin / Limbutara, Kavee / Kao, Anika R / Clark, Jevin Z / Nein, Ellen H / Raghuram, Viswanathan / Knepper, Mark A

American journal of physiology. Renal physiology

2024 Volume 326, Issue 3, Page(s) F545–F559

Abstract: Prior studies showed that epidermal growth factor (EGF) inhibits vasopressin-stimulated osmotic water permeability in the renal collecting duct. Here, we investigated the underlying mechanism. Using isolated perfused rat inner medullary collecting ducts ( ...

Abstract	Prior studies showed that epidermal growth factor (EGF) inhibits vasopressin-stimulated osmotic water permeability in the renal collecting duct. Here, we investigated the underlying mechanism. Using isolated perfused rat inner medullary collecting ducts (IMCDs), we found that the addition of EGF to the peritubular bath significantly decreased 1-deamino-8-d-arginine vasopressin (dDAVP)-stimulated water permeability, confirming prior observations. The inhibitory effect of EGF on water permeability was associated with a reduction in intracellular cAMP levels and protein kinase A (PKA) activity. Using phospho-specific antibodies and immunoblotting in IMCD suspensions, we showed that EGF significantly reduces phosphorylation of AQP2 at Ser
MeSH term(s)	Rats ; Animals ; Phosphorylation ; Aquaporin 2/metabolism ; Deamino Arginine Vasopressin/pharmacology ; Epidermal Growth Factor/pharmacology ; Epidermal Growth Factor/metabolism ; Water/metabolism ; Rats, Sprague-Dawley ; Bayes Theorem ; Kidney Tubules, Collecting/metabolism ; Vasopressins/pharmacology ; Protein Kinases/metabolism ; Permeability
Chemical Substances	Aquaporin 2 ; Deamino Arginine Vasopressin (ENR1LLB0FP) ; Epidermal Growth Factor (62229-50-9) ; Water (059QF0KO0R) ; Vasopressins (11000-17-2) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2024-01-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00197.2023
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Article ; Online: Targeted Single-Cell RNA-seq Identifies Minority Cell Types of Kidney Distal Nephron.

Chen, Lihe / Chou, Chun-Lin / Knepper, Mark A

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 4, Page(s) 886–896

Abstract: Background: Proximal tubule cells dominate the kidney parenchyma numerically, although less abundant cell types of the distal nephron have disproportionate roles in water and electrolyte balance.: Methods: Coupling of a FACS-based enrichment protocol ...

Abstract	Background: Proximal tubule cells dominate the kidney parenchyma numerically, although less abundant cell types of the distal nephron have disproportionate roles in water and electrolyte balance. Methods: Coupling of a FACS-based enrichment protocol with single-cell RNA-seq profiled the transcriptomes of 9099 cells from the thick ascending limb (CTAL)/distal convoluted tubule (DCT) region of the mouse nephron. Results: Unsupervised clustering revealed Conclusions: Single-cell transcriptomics revealed unexpected diversity among the cells of the distal nephron in mouse. Web-based data resources are provided for the single-cell data.
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2020101407
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Article ; Online: A resource database for protein kinase substrate sequence-preference motifs based on large-scale mass spectrometry data.

Poll, Brian G / Leo, Kirby T / Deshpande, Venky / Jayatissa, Nipun / Pisitkun, Trairak / Park, Euijung / Yang, Chin-Rang / Raghuram, Viswanathan / Knepper, Mark A

Cell communication and signaling : CCS

2024 Volume 22, Issue 1, Page(s) 137

Abstract: Background: Protein phosphorylation is one of the most prevalent posttranslational modifications involved in molecular control of cellular processes, and is mediated by over 520 protein kinases in humans and other mammals. Identification of the protein ... ...

Abstract	Background: Protein phosphorylation is one of the most prevalent posttranslational modifications involved in molecular control of cellular processes, and is mediated by over 520 protein kinases in humans and other mammals. Identification of the protein kinases responsible for phosphorylation events is key to understanding signaling pathways. Unbiased phosphoproteomics experiments have generated a wealth of data that can be used to identify protein kinase targets and their preferred substrate sequences. Methods: This study utilized prior data from mass spectrometry-based studies identifying sites of protein phosphorylation after in vitro incubation of protein mixtures with recombinant protein kinases. PTM-Logo software was used with these data to generate position-dependent Shannon information matrices and sequence motif 'logos'. Webpages were constructed for facile access to logos for each kinase and a new stand-alone application was written in Python that uses the position-dependent Shannon information matrices to identify kinases most likely to phosphorylate a particular phosphorylation site. Results: A database of kinase substrate target preference logos allows browsing, searching, or downloading target motif data for each protein kinase ( https://esbl.nhlbi.nih.gov/Databases/Kinase_Logos/ ). These logos were combined with phylogenetic analysis of protein kinase catalytic sequences to reveal substrate preference patterns specific to particular groups of kinases ( https://esbl.nhlbi.nih.gov/Databases/Kinase_Logos/KinaseTree.html ). A stand-alone program, KinasePredictor, is provided ( https://esbl.nhlbi.nih.gov/Databases/Kinase_Logos/KinasePredictor.html ). It takes as input, amino-acid sequences surrounding a given phosphorylation site and generates a ranked list of protein kinases most likely to phosphorylate that site. Conclusions: This study provides three new resources for protein kinase characterization. It provides a tool for prediction of kinase-substrate interactions, which in combination with other types of data (co-localization, etc.), can predict which kinases are likely responsible for a given phosphorylation event in a given tissue. Video Abstract.
MeSH term(s)	Animals ; Humans ; Phylogeny ; Protein Kinases/metabolism ; Phosphorylation ; Proteins/metabolism ; Mass Spectrometry/methods ; Mammals/metabolism
Chemical Substances	Protein Kinases (EC 2.7.-) ; Proteins
Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Video-Audio Media ; Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-023-01436-2
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Article ; Online: Systems biology of diuretic resistance.

Knepper, Mark A

The Journal of clinical investigation

2015 Volume 125, Issue 5, Page(s) 1793–1795

Abstract: Diuretics are commonly used to treat hypertension and extracellular fluid volume expansion. However, the development of compensatory responses in the kidney limits the benefit of this class of drugs. In this issue of the JCI, Grimm and colleagues use a ... ...

Abstract	Diuretics are commonly used to treat hypertension and extracellular fluid volume expansion. However, the development of compensatory responses in the kidney limits the benefit of this class of drugs. In this issue of the JCI, Grimm and colleagues use a systems biology approach in mice lacking the kinase SPAK and unravel a complex mechanism that explains thiazide diuretic resistance. The overall process involves interactions among six different cell types in the kidney.
MeSH term(s)	Animals ; Blood Pressure/physiology ; Chlorides/urine ; Gitelman Syndrome/physiopathology ; Male ; Natriuresis/physiology ; Nephrons/metabolism ; Renal Reabsorption/physiology
Chemical Substances	Chlorides
Language	English
Publishing date	2015-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI81505
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