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Article ; Online: Breaking New Ground: The Crucial Role of Animal Research in the Advancement of Rhabdomyolysis-Induced AKI Treatment and Prevention.

Semenikhina, Marharyta / Lipschutz, Joshua H / Palygin, Oleg

Function (Oxford, England)

2023 Volume 4, Issue 5, Page(s) zqad039

MeSH term(s)	Animals ; Endothelin-1/adverse effects ; Animal Experimentation ; Rhabdomyolysis/chemically induced ; Acute Kidney Injury/etiology ; Kidney
Chemical Substances	Endothelin-1
Language	English
Publishing date	2023-07-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
ISSN	2633-8823
ISSN (online)	2633-8823
DOI	10.1093/function/zqad039
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Article: The role of the exocyst in renal ciliogenesis, cystogenesis, tubulogenesis, and development.

Lipschutz, Joshua H

Kidney research and clinical practice

2019 Volume 38, Issue 3, Page(s) 260–266

Abstract: The exocyst is a highly conserved eight-subunit protein complex (EXOC1-8) involved in the targeting and docking of exocytic vesicles translocating from the trans-Golgi network to various sites in renal cells. EXOC5 is a central exocyst component because ... ...

Abstract	The exocyst is a highly conserved eight-subunit protein complex (EXOC1-8) involved in the targeting and docking of exocytic vesicles translocating from the trans-Golgi network to various sites in renal cells. EXOC5 is a central exocyst component because it connects EXOC6, bound to the vesicles exiting the trans-Golgi network via the small GTPase RAB8, to the rest of the exocyst complex at the plasma membrane. In the kidney, the exocyst complex is involved in primary ciliognesis, cystogenesis, and tubulogenesis. The exocyst, and its regulators, have also been found in urinary extracellular vesicles, and may be centrally involved in urocrine signaling and repair following acute kidney injury. The exocyst is centrally involved in the development of other organs, including the eye, ear, and heart. The exocyst is regulated by many different small GTPases of the RHO, RAL, RAB, and ARF families. The small GTPases, and their guanine nucleotide exchange factors and GTPase-activating proteins, likely give the exocyst specificity of function. The recent development of a floxed Exoc5 mouse line will aid researchers in studying the role of the exocyst in multiple cells and organ types by allowing for tissue-specific knockout, in conjunction with Cre-driver mouse lines.
Language	English
Publishing date	2019-07-05
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	2656420-8
ISSN	2211-9132
ISSN	2211-9132
DOI	10.23876/j.krcp.19.050
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Article ; Online: Role of the β

Arif, Ehtesham / Solanki, Ashish K / Rahman, Bushra / Wolf, Bethany / Schnellmann, Rick G / Nihalani, Deepak / Lipschutz, Joshua H

Pharmacological reports : PR

2024

Abstract: Background: Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β: Methods: We genetically deleted the β: ... ...

Abstract	Background: Podocytes have a remarkable ability to recover from injury; however, little is known about the recovery mechanisms involved in this process. We recently showed that formoterol, a long-acting β Methods: We genetically deleted the β Results: A similar level of injury was observed in β Conclusions: These results indicate that the podocyte β
Language	English
Publishing date	2024-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2186248-5
ISSN	2299-5684 ; 1734-1140
ISSN (online)	2299-5684
ISSN	1734-1140
DOI	10.1007/s43440-024-00594-5
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Zs.A 861: Show issues

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Article ; Online: The role of the exocyst in renal ciliogenesis, cystogenesis, tubulogenesis, and development

Joshua H. Lipschutz

Kidney Research and Clinical Practice, Vol 38, Iss 3, Pp 260-

2019 Volume 266

Abstract	The exocyst is a highly conserved eight-subunit protein complex (EXOC1-8) involved in the targeting and docking of exocytic vesicles translocating from the trans-Golgi network to various sites in renal cells. EXOC5 is a central exocyst component because it connects EXOC6, bound to the vesicles exiting the trans-Golgi network via the small GTPase RAB8, to the rest of the exocyst complex at the plasma membrane. In the kidney, the exocyst complex is involved in primary ciliognesis, cystogenesis, and tubulogenesis. The exocyst, and its regulators, have also been found in urinary extracellular vesicles, and may be centrally involved in urocrine signaling and repair following acute kidney injury. The exocyst is centrally involved in the development of other organs, including the eye, ear, and heart. The exocyst is regulated by many different small GTPases of the RHO, RAL, RAB, and ARF families. The small GTPases, and their guanine nucleotide exchange factors and GTPase-activating proteins, likely give the exocyst specificity of function. The recent development of a floxed Exoc5 mouse line will aid researchers in studying the role of the exocyst in multiple cells and organ types by allowing for tissue-specific knockout, in conjunction with Cre-driver mouse lines.
Keywords	Ciliogenesis ; Exocyst ; Exocytosis ; Sec6/8 complex ; Internal medicine ; RC31-1245 ; Specialties of internal medicine ; RC581-951
Subject code	571
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	The Korean Society of Nephrology
Document type	Article ; Online
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Article: Hydrogen sulfide, a gaseous signaling molecule, elongates primary cilia on kidney tubular epithelial cells by activating extracellular signal-regulated kinase.

Han, Sang Jun / Kim, Jee In / Lipschutz, Joshua H / Park, Kwon Moo

The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology

2021 Volume 25, Issue 6, Page(s) 593–601

Abstract: ... on oxidative stress and extracellular signal-regulated kinase 1/2 (ERK) activation. Hydrogen sulfide (H ...

Abstract	Primary cilia on kidney tubular cells play crucial roles in maintaining structure and physiological function. Emerging evidence indicates that the absence of primary cilia, and their length, are associated with kidney diseases. The length of primary cilia in kidney tubular epithelial cells depends, at least in part, on oxidative stress and extracellular signal-regulated kinase 1/2 (ERK) activation. Hydrogen sulfide (H
Language	English
Publishing date	2021-10-25
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	1387595-4
ISSN	2093-3827 ; 1226-4512
ISSN (online)	2093-3827
ISSN	1226-4512
DOI	10.4196/kjpp.2021.25.6.593
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Article: Shortening of primary cilia length is associated with urine concentration in the kidneys.

Kong, Min Jung / Han, Sang Jun / Seu, Sung Young / Han, Ki-Hwan / Lipschutz, Joshua H / Park, Kwon Moo

Kidney research and clinical practice

2023 Volume 42, Issue 3, Page(s) 312–324

Abstract: Background: The primary cilium, a microtubule-based cellular organelle present in certain kidney cells, functions as a mechano-sensor to monitor fluid flow in addition to various other biological functions. In kidneys, the primary cilia protrude into ... ...

Abstract	Background: The primary cilium, a microtubule-based cellular organelle present in certain kidney cells, functions as a mechano-sensor to monitor fluid flow in addition to various other biological functions. In kidneys, the primary cilia protrude into the tubular lumen and are directly exposed to pro-urine flow and components. However, their effects on urine concentration remain to be defined. Here, we investigated the association between primary cilia and urine concentration. Methods: Mice either had free access to water (normal water intake, NWI) or were not allowed access to water (water deprivation, WD). Some mice received tubastatin, an inhibitor of histone deacetylase 6 (HDAC6), which regulates the acetylation of α-tubulin, a core protein of microtubules. Results: WD decreased urine output and increased urine osmolality, concomitant with apical plasma membrane localization of aquaporin 2 (AQP2) in the kidney. After WD, compared with after NWI, the lengths of primary cilia in renal tubular epithelial cells were shortened and HDAC6 activity increased. WD induced deacetylation of α-tubulin without altering α-tubulin levels in the kidney. Tubastatin prevented the shortening of cilia through increasing HDAC6 activity and consequently increasing acetylated α-tubulin expression. Furthermore, tubastatin prevented the WD-induced reduction of urine output, urine osmolality increase, and apical plasma membrane localization of AQP2. Conclusions: WD shortens primary cilia length through HDAC6 activation and α-tubulin deacetylation, while HDAC6 inhibition blocks the WD-induced changes in cilia length and urine output. This suggests that cilia length alterations are involved, at least in part, in the regulation of body water balance and urine concentration.
Language	English
Publishing date	2023-05-31
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2656420-8
ISSN	2211-9132
ISSN	2211-9132
DOI	10.23876/j.krcp.22.274
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Article: High water intake induces primary cilium elongation in renal tubular cells.

Kong, Min Jung / Han, Sang Jun / Seu, Sung Young / Han, Ki-Hwan / Lipschutz, Joshua H / Park, Kwon Moo

Kidney research and clinical practice

2023

Abstract: Background: The primary cilium protrudes from the cell surface and functions as a mechanosensor. Recently, we found that water intake restriction shortens the primary cilia of renal tubular cells, and a blockage of the shortening disturbs the ability of ...

Abstract	Background: The primary cilium protrudes from the cell surface and functions as a mechanosensor. Recently, we found that water intake restriction shortens the primary cilia of renal tubular cells, and a blockage of the shortening disturbs the ability of the kidneys to concentrate urine. Here, we investigate whether high water intake (HWI) alters primary cilia length, and if so, what is its underlying mechanism and its role on kidney urine production. Methods: Experimental mice were given free access to normal water (normal water intake) or 3% sucrose-containing water for HWI for 2 days. Some mice were administered with U0126 (10 mg/kg body weight), an inhibitor of MEK kinase, from 2 days before HWI, daily. The primary cilium length and urine amount and osmolality were investigated. Results: HWI-induced diluted urine production and primary cilium elongation in renal tubular cells. HWI increased the expression of α-tubulin acetyltransferase 1 (αTAT1), leading to the acetylation of α-tubulins, a core protein of the primary cilia. HWI also increased phosphorylated ERK1/2 (p-ERK1/2) and exocyst complex component 5 (EXOC5) expression in the kidneys. U0126 blocked HWI-induced increases in αTAT1, p-ERK1/2, and EXOC5 expression. U0126 inhibited HWI-induced α-tubulin acetylation, primary cilium elongation, urine amount increase, and urine osmolality decrease. Conclusion: These results show that increased water intake elongates the primary cilia via ERK1/2 activation and that ERK inhibition prevents primary cilium elongation and diluted urine production. These data suggest that the elongation of primary cilium length is associated with the production of diluted urine.
Language	English
Publishing date	2023-11-07
Publishing country	Korea (South)
Document type	Journal Article
ZDB-ID	2656420-8
ISSN	2211-9132
ISSN	2211-9132
DOI	10.23876/j.krcp.23.087
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Article ; Online: β

Arif, Ehtesham / Medunjanin, Danira / Solanki, Ashish / Zuo, Xiaofeng / Su, Yanhui / Dang, Yujing / Winkler, Brennan / Lerner, Kasey / Kamal, Ahmed I / Palygin, Oleg / Cornier, Marc-Andre / Wolf, Bethany J / Hunt, Kelly J / Lipschutz, Joshua H

American journal of physiology. Renal physiology

2023 Volume 326, Issue 1, Page(s) F20–F29

Abstract: We have previously shown that the long-acting ... ...

Abstract	We have previously shown that the long-acting β
MeSH term(s)	Humans ; Animals ; Mice ; Diabetic Nephropathies/drug therapy ; Adrenergic beta-2 Receptor Agonists/therapeutic use ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/drug therapy ; Streptozocin ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Formoterol Fumarate/therapeutic use ; Kidney Failure, Chronic/drug therapy ; Kidney Failure, Chronic/etiology ; Receptors, Adrenergic/therapeutic use
Chemical Substances	Adrenergic beta-2 Receptor Agonists ; Streptozocin (5W494URQ81) ; Formoterol Fumarate (W34SHF8J2K) ; Receptors, Adrenergic
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; 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.00254.2023
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Article: Tubule and cyst formation: lightning strikes twice.

Lipschutz, Joshua H

American journal of physiology. Renal physiology

2009 Volume 296, Issue 3, Page(s) F477

MeSH term(s)	Animals ; Disease Models, Animal ; Dogs ; Kidney Tubules/pathology ; Mice ; Polycystic Kidney Diseases/physiopathology
Language	English
Publishing date	2009-03
Publishing country	United States
Document type	Editorial
ZDB-ID	603837-2
ISSN	1522-1466 ; 1931-857X ; 0363-6127
ISSN (online)	1522-1466
ISSN	1931-857X ; 0363-6127
DOI	10.1152/ajprenal.00001.2009
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Article ; Online: β-Arrestin pathway activation by selective ATR1 agonism promotes calcium influx in podocytes, leading to glomerular damage.

Semenikhina, Marharyta / Fedoriuk, Mykhailo / Stefanenko, Mariia / Klemens, Christine A / Cherezova, Alena / Marshall, Brendan / Hall, Gentzon / Levchenko, Vladislav / Solanki, Ashish K / Lipschutz, Joshua H / Ilatovskaya, Daria V / Staruschenko, Alexander / Palygin, Oleg

Clinical science (London, England : 1979)

2023 Volume 137, Issue 24, Page(s) 1789–1804

Abstract: Angiotensin receptor blockers (ARBs) are the first-line treatment for hypertension; they act by inhibiting signaling through the angiotensin 1 receptor (AT1R). Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the β- ... ...

Abstract	Angiotensin receptor blockers (ARBs) are the first-line treatment for hypertension; they act by inhibiting signaling through the angiotensin 1 receptor (AT1R). Recently, a novel biased AT1R agonist, TRV120027 (TRV), which selectively activates the β-arrestin cascade and blocks the G-protein-coupled receptor pathway has been proposed as a potential blood pressure medication. Here, we explored the effects of TRV and associated β-arrestin signaling in podocytes, essential cells of the kidney filter. We used human podocyte cell lines to determine β-arrestin's involvement in calcium signaling and cytoskeletal reorganization and Dahl SS rats to investigate the chronic effects of TRV administration on glomerular health. Our experiments indicate that the TRV-activated β-arrestin pathway promotes the rapid elevation of intracellular Ca2+ in a dose-dependent manner. Interestingly, the amplitude of β-arrestin-mediated Ca2+ influx was significantly higher than the response to similar Ang II concentrations. Single-channel analyses show rapid activation of transient receptor potential canonical (TRPC) channels following acute TRV application. Furthermore, the pharmacological blockade of TRPC6 significantly attenuated the β-arrestin-mediated Ca2+ influx. Additionally, prolonged activation of the β-arrestin pathway in podocytes resulted in pathological actin cytoskeleton rearrangements, higher apoptotic cell markers, and augmented glomerular damage. TRV-activated β-arrestin signaling in podocytes may promote TRPC6 channel-mediated Ca2+ influx, foot process effacement, and apoptosis, possibly leading to severe defects in glomerular filtration barrier integrity and kidney health. Under these circumstances, the potential therapeutic application of TRV for hypertension treatment requires further investigation to assess the balance of the benefits versus possible deleterious effects and off-target damage.
MeSH term(s)	Rats ; Animals ; Humans ; Podocytes/metabolism ; TRPC6 Cation Channel/metabolism ; Calcium/metabolism ; beta-Arrestins/metabolism ; Angiotensin Receptor Antagonists/pharmacology ; Rats, Inbred Dahl ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Kidney Diseases/metabolism ; Hypertension/metabolism ; TRPC Cation Channels/metabolism ; TRPC Cation Channels/pharmacology
Chemical Substances	TRPC6 Cation Channel ; Calcium (SY7Q814VUP) ; beta-Arrestins ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; TRPC Cation Channels
Language	English
Publishing date	2023-12-05
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	206835-7
ISSN	1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
ISSN (online)	1470-8736
ISSN	0301-0538 ; 0009-0360 ; 0143-5221
DOI	10.1042/CS20230313
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