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Article ; Online: Leucine-Rich Repeat in Polycystin-1 Suppresses Cystogenesis in a Zebrafish (

Padhy, Biswajit / Amir, Mohammad / Xie, Jian / Huang, Chou-Long

International journal of molecular sciences

2024 Volume 25, Issue 5

Abstract: Mutations ... ...

Abstract	Mutations of
MeSH term(s)	Animals ; Humans ; Polycystic Kidney, Autosomal Dominant/genetics ; Zebrafish/genetics ; Leucine/metabolism ; TRPP Cation Channels/metabolism ; Polycystic Kidney Diseases/metabolism ; Laminin/metabolism ; Kidney/metabolism
Chemical Substances	Leucine (GMW67QNF9C) ; TRPP Cation Channels ; Laminin
Language	English
Publishing date	2024-03-01
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/ijms25052886
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Article: Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.

Cheng, Chih-Jen / Nizar, Jonathan M / Dai, Dao-Fu / Huang, Chou-Long

bioRxiv : the preprint server for biology

2024

Abstract: Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial ... ...

Abstract	Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) predominantly utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity. Key points: A positive correlation between salt reabsorption and oxygen consumption in mammalian kidneys hints at a potential interaction between transport activity and mitochondrial respiration in renal tubules.Renal tubules are heterogeneous in transport activity and mitochondrial metabolism, and traditional assays using bulk kidney tissues cannot provide segment-specific information.Here, we applied an extracellular flux analysis to investigate mitochondrial respiration and energy metabolism in isolated renal tubules. This assay is sensitive in detecting oxygen consumption and acid production in centimeter-length renal tubules and reliably recapitulates segment-specific metabolic features.Acute inhibition of transport activity reduces basal and ATP-linked mitochondrial respirations without changing maximal mitochondrial respiratory capacity. Chronic alterations of transport activity further adjust maximal mitochondrial respiratory capacity via regulating mitochondrial biogenesis or non-transcriptional mechanisms.Our findings support the concept that renal tubular cells finely adjust mitochondrial bioenergetics and biogenesis to match the new steady state of transport activity.
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.04.578838
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Article ; Online: LRRC8A reduces intracellular chloride to permit WNK activation in response to hypertonic stress.

Goldsmith, Elizabeth J / Huang, Chou-Long

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

2021 Volume 118, Issue 32

MeSH term(s)	Carrier Proteins ; Chlorides/metabolism ; Osmotic Pressure
Chemical Substances	Carrier Proteins ; Chlorides
Language	English
Publishing date	2021-08-06
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2109432118
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Article: Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy.

Schnicker, Nicholas J / Xu, Zhen / Amir, Mohammad / Gakhar, Lokesh / Huang, Chou-Long

bioRxiv : the preprint server for biology

2024

Abstract: α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic ... ...

Abstract	α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Single particle cryogenic electron microscopy (cryo-EM) supported the dimeric structure of sKLA. Cryo-EM further revealed a 3.3Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. 3D variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. A comprehensive understanding of the sKLA conformational landscape will provide the foundation for developing klotho-related therapies for diseases.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.02.583144
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Article: WNK1-OSR1/SPAK KINASE CASCADE IS IMPORTANT FOR ANGIOGENESIS.

Huang, Chou-Long / Jian, Xie / Yuh, Chiou-Hwa

Transactions of the American Clinical and Climatological Association

2020 Volume 131, Page(s) 140–146

Abstract: WNK [with-no-lysine (K)] kinases are a family of four members of serine and threonine kinases that regulate renal ... ...

Abstract	WNK [with-no-lysine (K)] kinases are a family of four members of serine and threonine kinases that regulate renal Na
Language	English
Publishing date	2020-07-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	603823-2
ISSN	0065-7778
ISSN	0065-7778
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Article ; Online: WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release

Xin Jin / Jian Xie / Chia-Wei Yeh / Jen-Chi Chen / Chih-Jen Cheng / Cheng-Chang Lien / Chou-Long Huang

The Journal of Clinical Investigation, Vol 133, Iss

2023 Volume 11

Abstract: Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) in response to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs (CVOs) of the brain focus on ... ...

Abstract	Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) in response to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs (CVOs) of the brain focus on mechanosensitive membrane proteins. The present study demonstrated that intracellular protein kinase WNK1 was involved. Focusing on vascular-organ-of-lamina-terminalis (OVLT) nuclei, we showed that WNK1 kinase was activated by water restriction. Neuron-specific conditional KO (cKO) of Wnk1 caused polyuria with decreased urine osmolality that persisted in water restriction and blunted water restriction–induced AVP release. Wnk1 cKO also blunted mannitol-induced AVP release but had no effect on osmotic thirst response. The role of WNK1 in the osmosensory neurons in CVOs was supported by neuronal pathway tracing. Hyperosmolality-induced increases in action potential firing in OVLT neurons was blunted by Wnk1 deletion or pharmacological WNK inhibitors. Knockdown of Kv3.1 channel in OVLT by shRNA reproduced the phenotypes. Thus, WNK1 in osmosensory neurons in CVOs detects extracellular hypertonicity and mediates the increase in AVP release by activating Kv3.1 and increasing action potential firing from osmosensory neurons.
Keywords	Endocrinology ; Nephrology ; Medicine ; R
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	American Society for Clinical Investigation
Document type	Article ; Online
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Article ; Online: Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease.

Padhy, Biswajit / Xie, Jian / Wang, Runping / Lin, Fang / Huang, Chou-Long

Journal of the American Society of Nephrology : JASN

2022 Volume 33, Issue 8, Page(s) 1501–1516

Abstract: Background: Mutations of : Methods: The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium ion release. Using TRIC-B ... ...

Abstract	Background: Mutations of Methods: The trimeric intracellular cation (TRIC) channel TRIC-B is an ER-resident potassium channel that mediates potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium ion release. Using TRIC-B as a tool, we examined the function of ER-localized polycystin-2 and its role in ADPKD pathogenesis in cultured cells, zebrafish, and mouse models. Results: Agonist-induced ER calcium ion release was defective in cells lacking polycystin-2 and reversed by exogenous expression of TRIC-B. Conclusions: Polycystin-2 in the ER appears to be critical for anticystogenesis and likely functions as a potassium ion channel to facilitate potassium-calcium counterion exchange for inositol trisphosphate-mediated calcium release. The results advance the understanding of ADPKD pathogenesis and provides proof of principle for pharmacotherapy by TRIC-B activators.
MeSH term(s)	Animals ; Calcium/metabolism ; Endoplasmic Reticulum/metabolism ; Inositol/metabolism ; Ion Channels/genetics ; Mice ; Polycystic Kidney, Autosomal Dominant/genetics ; Polycystic Kidney, Autosomal Dominant/metabolism ; Polycystic Kidney, Autosomal Dominant/prevention & control ; Potassium/metabolism ; Potassium Channels ; TRPP Cation Channels/genetics ; TRPP Cation Channels/metabolism ; Zebrafish/metabolism
Chemical Substances	Ion Channels ; Potassium Channels ; TRIC-B protein, mouse ; TRPP Cation Channels ; Inositol (4L6452S749) ; Potassium (RWP5GA015D) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-07-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2022010053
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Zs.A 3344: Show issues

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Article ; Online: WNK1 promotes water homeostasis by acting as a central osmolality sensor for arginine vasopressin release.

Jin, Xin / Xie, Jian / Yeh, Chia-Wei / Chen, Jen-Chi / Cheng, Chih-Jen / Lien, Cheng-Chang / Huang, Chou-Long

The Journal of clinical investigation

2023 Volume 133, Issue 11

Abstract	Maintaining internal osmolality constancy is essential for life. Release of arginine vasopressin (AVP) in response to hyperosmolality is critical. Current hypotheses for osmolality sensors in circumventricular organs (CVOs) of the brain focus on mechanosensitive membrane proteins. The present study demonstrated that intracellular protein kinase WNK1 was involved. Focusing on vascular-organ-of-lamina-terminalis (OVLT) nuclei, we showed that WNK1 kinase was activated by water restriction. Neuron-specific conditional KO (cKO) of Wnk1 caused polyuria with decreased urine osmolality that persisted in water restriction and blunted water restriction-induced AVP release. Wnk1 cKO also blunted mannitol-induced AVP release but had no effect on osmotic thirst response. The role of WNK1 in the osmosensory neurons in CVOs was supported by neuronal pathway tracing. Hyperosmolality-induced increases in action potential firing in OVLT neurons was blunted by Wnk1 deletion or pharmacological WNK inhibitors. Knockdown of Kv3.1 channel in OVLT by shRNA reproduced the phenotypes. Thus, WNK1 in osmosensory neurons in CVOs detects extracellular hypertonicity and mediates the increase in AVP release by activating Kv3.1 and increasing action potential firing from osmosensory neurons.
MeSH term(s)	Arginine Vasopressin/genetics ; Homeostasis ; Osmolar Concentration ; Thirst/physiology ; Water
Chemical Substances	Arginine Vasopressin (113-79-1) ; Water (059QF0KO0R)
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI164222
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Article: Regulation of ion channels by secreted Klotho.

Huang, Chou-Long

Advances in experimental medicine and biology

2012 Volume 728, Page(s) 100–106

Abstract: Klotho is an anti-aging protein predominantly expressed in the kidney, parathyroid glands and choroid plexus of the brain. Klotho exists in two forms, a membrane form and a soluble secreted form. Recent studies show that the secreted Klotho possess ... ...

Abstract	Klotho is an anti-aging protein predominantly expressed in the kidney, parathyroid glands and choroid plexus of the brain. Klotho exists in two forms, a membrane form and a soluble secreted form. Recent studies show that the secreted Klotho possess sialidase activity and regulates several ion channels via the activity. Removal of terminal sialic acids from N-glycan chains of the epithelial Ca(2+) channel TRPV5 and the renal K(+) channel ROMK by secreted Klotho exposes the underlying disaccharide galactose-N-acetylglucosamine, a ligand for galectin-1. Binding to galectin-1 at the extracellular surface prevents internalization and leads to accumulation of the channels on the plasma membrane. Future studies will investigate whether secreted Klotho regulates cell-surface expression of other membrane glycoproteins via the same mechanism.
MeSH term(s)	Aging/metabolism ; Animals ; Cell Membrane/metabolism ; Glucuronidase/chemistry ; Glucuronidase/metabolism ; Glucuronidase/secretion ; Humans ; Ion Channels/metabolism ; Sequence Homology, Amino Acid
Chemical Substances	Ion Channels ; Glucuronidase (EC 3.2.1.31) ; klotho protein (EC 3.2.1.31)
Language	English
Publishing date	2012
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/978-1-4614-0887-1_7
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Article ; Online: Glucosylceramide synthase inhibition protects against cardiac hypertrophy in chronic kidney disease

Gabriel C. Baccam / Jian Xie / Xin Jin / Hyejung Park / Bing Wang / Hervé Husson / Oxana Ibraghimov-Beskrovnaya / Chou-Long Huang

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 15

Abstract: Abstract A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, ... ...

Abstract	Abstract A significant population of patients with chronic kidney disease (CKD) develops cardiac hypertrophy, which can lead to heart failure and sudden cardiac death. Soluble klotho (sKL), the shed ectodomain of the transmembrane protein klotho, protects the heart against hypertrophic growth. We have shown that sKL protects the heart by regulating the formation and function of lipid rafts by targeting the sialic acid moiety of gangliosides, GM1/GM3. Reduction in circulating sKL contributes to an increased risk of cardiac hypertrophy in mice. sKL replacement therapy has been considered but its use is limited by the inability to mass produce the protein. Therefore, alternative methods to protect the heart are proposed. Glucosylation of ceramide catalyzed by glucosylceramide synthase is the entry step for the formation of gangliosides. Here we show that oral administration of a glucosylceramide synthase inhibitor (GCSi) reduces plasma and heart tissue glycosphingolipids, including gangliosides. Administration of GCSi is protective in two mouse models of cardiac stress-induction, one with isoproterenol overstimulation and the other with 5/6 nephrectomy-induced CKD. Treatment with GCSi does not alter the severity of renal dysfunction and hypertension in CKD. These results provide proof of principle for targeting glucosylceramide synthase to decrease gangliosides as a treatment for cardiac hypertrophy. They also support the hypothesis that sKL protects the heart by targeting gangliosides.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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