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Article ; Online: Role of actin cytoskeleton in podocytes.

Sever, Sanja

2020 Volume 36, Issue 9, Page(s) 2607–2614

Abstract: The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells, the glomerular basement membrane, and podocytes. Functional impairment or injury of ... ...

Abstract	The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells, the glomerular basement membrane, and podocytes. Functional impairment or injury of any of these three components can lead to proteinuria. Podocytes are injured in many forms of human and experimental glomerular disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetes mellitus. One of the earliest signs of podocyte injury is loss of their distinct structure, which is driven by dysregulated dynamics of the actin cytoskeleton. The status of the actin cytoskeleton in podocytes depends on a set of actin binding proteins, nucleators and inhibitors of actin polymerization, and regulatory GTPases. Mutations that alter protein function in each category have been implicated in glomerular diseases in humans and animal models. In addition, a growing body of studies suggest that pharmacological modifications of the actin cytoskeleton have the potential to become novel therapeutics for podocyte-dependent chronic kidney diseases. This review presents an overview of the essential proteins that establish actin cytoskeleton in podocytes and studies demonstrating the feasibility of drugging actin cytoskeleton in kidney diseases.
MeSH term(s)	Actin Cytoskeleton/physiology ; Animals ; Humans ; Podocytes/metabolism
Language	English
Publishing date	2020-11-13
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-020-04812-z
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Article ; Online: Actin dynamics at focal adhesions: a common endpoint and putative therapeutic target for proteinuric kidney diseases.

Sever, Sanja / Schiffer, Mario

Kidney international

2018 Volume 93, Issue 6, Page(s) 1298–1307

Abstract: Proteinuria encompasses diverse causes including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely ... ...

Abstract	Proteinuria encompasses diverse causes including both genetic diseases and acquired forms such as diabetic and hypertensive nephropathy. The basis of proteinuria is a disturbance in size selectivity of the glomerular filtration barrier, which largely depends on the podocyte: a terminally differentiated epithelial cell type covering the outer surface of the glomerulus. Compromised podocyte structure is one of the earliest signs of glomerular injury. The phenotype of diverse animal models and podocyte cell culture firmly established the essential role of the actin cytoskeleton in maintaining functional podocyte structure. Podocyte foot processes, actin-based membrane extensions, contain 2 molecularly distinct "hubs" that control actin dynamics: a slit diaphragm and focal adhesions. Although loss of foot processes encompasses disassembly of slit diaphragm multiprotein complexes, as long as cells are attached to the glomerular basement membrane, focal adhesions will be the sites in which stress due to filtration flow is counteracted by forces generated by the actin network in foot processes. Numerous studies within last 20 years have identified actin binding and regulatory proteins as well as integrins as essential components of signaling and actin dynamics at focal adhesions in podocytes, suggesting that some of them may become novel, druggable targets for proteinuric kidney diseases. Here we review evidence supporting the idea that current treatments for chronic kidney diseases beneficially and directly target the podocyte actin cytoskeleton associated with focal adhesions and suggest that therapeutic reagents that target the focal adhesion-regulated actin cytoskeleton in foot processes have potential to modernize treatments for chronic kidney diseases.
MeSH term(s)	Actin Cytoskeleton/drug effects ; Actin Cytoskeleton/metabolism ; Actin Cytoskeleton/pathology ; Actins/metabolism ; Animals ; Focal Adhesions/drug effects ; Focal Adhesions/metabolism ; Focal Adhesions/pathology ; Glomerular Basement Membrane/drug effects ; Glomerular Basement Membrane/metabolism ; Glomerular Basement Membrane/pathology ; Glomerular Basement Membrane/physiopathology ; Glomerular Filtration Rate ; Humans ; Molecular Targeted Therapy ; Podocytes/drug effects ; Podocytes/metabolism ; Podocytes/pathology ; Proteinuria/drug therapy ; Proteinuria/genetics ; Proteinuria/metabolism ; Proteinuria/pathology ; Renal Agents/therapeutic use ; Renal Insufficiency, Chronic/drug therapy ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/metabolism ; Renal Insufficiency, Chronic/pathology ; Signal Transduction
Chemical Substances	Actins ; Renal Agents
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2017.12.028
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Article ; Online: Economic Sentiment Perceptions During COVID-19 Pandemic – A European Cross-Country Impact Assessment

Iustina Alina Boitan / Emilia Mioara Câmpeanu / Sanja Sever Mališ

Amfiteatru Economic, Vol 23, Iss Special Issue No. 15, Pp 982-

2021 Volume 1002

Abstract: An increasing body of recent literature focuses on how stock market investor sentiment fluctuates during the pandemic. However, a topic insufficiently addressed is related to investigating the changes occurred in the economic sentiment and expectations ... ...

Abstract	An increasing body of recent literature focuses on how stock market investor sentiment fluctuates during the pandemic. However, a topic insufficiently addressed is related to investigating the changes occurred in the economic sentiment and expectations during COVID-19 pandemic, as a broader concept than stock market investors' perception and expectations. The paper investigates the impact of COVID-19 pandemic on the economic sentiment pattern in European Union countries, through two complementary research approaches: an exploratory data analysis technique represented by a hierarchic agglomerative clustering and a probabilistic GLM panel regression framework. Several official survey-based economic sentiment indices (Economic sentiment indicator, Employment expectations index, Composite leading indicator, Business confidence index, Consumer confidence index) are included in the empirical analysis to comprehensively reflect businesses and consumers’ current economic and employment perceptions and expectations on future developments. The clustering solution indicates increased heterogeneity among European countries and no stable group. The sentiment related to the employment consequences of the COVID-19 crisis records the sharpest fluctuation and is reflected in countries’ classification. The panel regression findings reveal that the number of new deaths is the most influential COVID-19 proxy variable, as it determines the evolution of most sentiment indicators.
Keywords	economic sentiment ; confidence index ; expectations ; covid-19 pandemic ; cluster analysis ; panel regression ; Business ; HF5001-6182 ; Economics as a science ; HB71-74
Subject code	332
Language	English
Publishing date	2021-11-01T00:00:00Z
Publisher	Academy of Economic Studies of Bucharest
Document type	Article ; Online
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Article ; Online: A Novel Fluorogenic Assay for the Detection of Nephrotoxin-Induced Oxidative Stress in Live Cells and Renal Tissue.

Mukherjee, Kamalika / Chio, Tak Ian / Gu, Han / Sackett, Dan L / Bane, Susan L / Sever, Sanja

ACS sensors

2021 Volume 6, Issue 7, Page(s) 2523–2528

Abstract: Drug-induced kidney injury frequently leads to aborted clinical trials and drug withdrawals. Sufficiently sensitive sensors capable of detecting mild signs of chemical insult in cell-based screening assays are critical to identifying and eliminating ... ...

Abstract	Drug-induced kidney injury frequently leads to aborted clinical trials and drug withdrawals. Sufficiently sensitive sensors capable of detecting mild signs of chemical insult in cell-based screening assays are critical to identifying and eliminating potential toxins in the preclinical stage. Oxidative stress is a common early manifestation of chemical toxicity, and biomolecule carbonylation is an irreversible repercussion of oxidative stress. Here, we present a novel fluorogenic assay using a sensor, TFCH, that responds to biomolecule carbonylation and efficiently detects modest forms of renal injury with much greater sensitivity than standard assays for nephrotoxins. We demonstrate that this sensor can be deployed in live kidney cells and in renal tissue. Our robust assay may help inform preclinical decisions to recall unsafe drug candidates. The application of this sensor in identifying and analyzing diverse pathologies is envisioned.
MeSH term(s)	Oxidative Stress
Language	English
Publishing date	2021-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2379-3694
ISSN (online)	2379-3694
DOI	10.1021/acssensors.1c00422
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Article ; Online: CD2AP, dendrin, and cathepsin L in the kidney.

Sever, Sanja / Reiser, Jochen

The American journal of pathology

2015 Volume 185, Issue 11, Page(s) 3129–3130

MeSH term(s)	Animals ; Kidney Diseases/genetics ; Kidney Failure, Chronic/genetics ; Longevity/genetics ; Nerve Tissue Proteins/genetics ; Podocytes/pathology
Chemical Substances	Nerve Tissue Proteins
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Comment ; Letter ; Research Support, N.I.H., Extramural
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2015.06.022
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Article ; Online: The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease.

Zhu, Ke / Mukherjee, Kamalika / Wei, Changli / Hayek, Salim S / Collins, Agnieszka / Gu, Changkyu / Corapi, Kristin / Altintas, Mehmet M / Wang, Yong / Waikar, Sushrut S / Bianco, Antonio C / Koch, Alexander / Tacke, Frank / Reiser, Jochen / Sever, Sanja

Science translational medicine

2023 Volume 15, Issue 714, Page(s) eabq6492

Abstract: Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, ... ...

Abstract	Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic β cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored β cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired β cell proliferation and inhibited the bioenergetics of β cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus.
MeSH term(s)	Animals ; Mice ; Humans ; Diabetes Mellitus, Type 1 ; Immunotoxins ; Receptors, Urokinase Plasminogen Activator ; Kidney Diseases ; Insulin ; Hyperglycemia
Chemical Substances	Immunotoxins ; Receptors, Urokinase Plasminogen Activator ; Insulin
Language	English
Publishing date	2023-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.abq6492
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Zs.A 6941: Show issues

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Article: The Stable Gastric Pentadecapeptide BPC 157 Pleiotropic Beneficial Activity and Its Possible Relations with Neurotransmitter Activity.

Pharmaceuticals (Basel, Switzerland)

2024 Volume 17, Issue 4

Abstract: We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically ...

Abstract	We highlight the particular aspects of the stable gastric pentadecapeptide BPC 157 pleiotropic beneficial activity (not destroyed in human gastric juice, native and stable in human gastric juice, as a cytoprotection mediator holds a response specifically related to preventing or recovering damage as such) and its possible relations with neurotransmitter activity. We attempt to resolve the shortage of the pleiotropic beneficial effects of BPC 157, given the general standard neurotransmitter criteria, in classic terms. We substitute the lack of direct conclusive evidence (i.e., production within the neuron or present in it as a precursor molecule, released eliciting a response on the receptor on the target cells on neurons and being removed from the site of action once its signaling role is complete). This can be a network of interconnected evidence, previously envisaged in the implementation of the cytoprotection effects, consistent beneficial particular evidence that BPC 157 therapy counteracts dopamine, serotonin, glutamate, GABA, adrenalin/noradrenalin, acetylcholine, and NO-system disturbances. This specifically includes counteraction of those disturbances related to their receptors, both blockade and over-activity, destruction, depletion, tolerance, sensitization, and channel disturbances counteraction. Likewise, BPC 157 activates particular receptors (i.e., VGEF and growth hormone). Furthermore, close BPC 157/NO-system relations with the gasotransmitters crossing the cell membrane and acting directly on molecules inside the cell may envisage particular interactions with receptors on the plasma membrane of their target cells. Finally, there is nerve-muscle relation in various muscle disturbance counteractions, and nerve-nerve relation in various encephalopathies counteraction, which is also exemplified specifically by the BPC 157 therapy application.
Language	English
Publishing date	2024-04-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph17040461
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Article: Recessive variants in the intergenic

Buerger, Florian / Salmanullah, Daanya / Liang, Lorrin / Gauntner, Victoria / Krueger, Kavita / Qi, Maggie / Sharma, Vineeta / Rubin, Alexander / Ball, David / Lemberg, Katharina / Saida, Ken / Merz, Lea Maria / Sever, Sanja / Issac, Biju / Sun, Liang / Guerrero-Castillo, Sergio / Gomez, Alexis C / McNulty, Michelle T / Sampson, Matthew G /

Al-Hamed, Mohamed H / Saleh, Mohammed M / Shalaby, Mohamed / Kari, Jameela / Fawcett, James P / Hildebrandt, Friedhelm / Majmundar, Amar J

medRxiv : the preprint server for health sciences

2024

Abstract: In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants ... ...

Abstract	In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.17.24303374
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Article ; Online: AUDIT MARKET CONCENTRATION – EVIDENCE FROM CROATIA

Sanja Sever Mališ / Mateja Brozović

Ekonomski Vjesnik, Vol 28, Iss 2, Pp 339-

2015 Volume 356

Abstract: Statutory audit is designated to protect the public interest and has a significant impact on the overall economy. There are concerns that the Big Four audit firms have become too dominant and that the collapse of one of these firms would disrupt the ... ...

Abstract	Statutory audit is designated to protect the public interest and has a significant impact on the overall economy. There are concerns that the Big Four audit firms have become too dominant and that the collapse of one of these firms would disrupt the whole financial system. In terms of revenues received, the total market share of the Big Four audit firms for listed companies exceeds 90% in a vast majority of European Union Member States. Prior studies have shown that high audit market concentration limits the choice of auditor for large companies and sets a high barrier of entry for mid-tier audit firms, while the effect on audit quality and audit fees is still unclear. Therefore, the regulators are considering reforms to dilute the Big Four’s dominance and improve competition in the audit market. The paper reviews the proposed and implemented measures that are the most common, together with their advantages and drawbacks. In addition, the characteristics of the audit market in Croatia are investigated, with a focus on market concentration measured by standard measures such as the Concentration rate, the Herfindahl Hirschman Index and the Gini coefficient. According to market shares based on total clients’ assets and revenues, the audit market for listed companies is moderately to highly concentrated, with a decrease in the five-year period (2013 compared to 2008).
Keywords	audit ; audit concentration ; Big Four audit firms ; audit market reforms ; audit market in Croatia ; Social Sciences ; H ; Economics as a science ; HB71-74
Subject code	650
Language	English
Publishing date	2015-12-01T00:00:00Z
Publisher	Faculty of Economics in Osijek
Document type	Article ; Online
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Article ; Online: The small GTPase regulatory protein Rac1 drives podocyte injury independent of cationic channel protein TRPC5.

Polat, Onur K / Isaeva, Elena / Sudhini, Yashwanth R / Knott, Brenna / Zhu, Ke / Noben, Manuel / Suresh Kumar, Varsha / Endlich, Nicole / Mangos, Steve / Reddy, Tejasree Vallapu / Samelko, Beata / Wei, Changli / Altintas, Mehmet M / Dryer, Stuart E / Sever, Sanja / Staruschenko, Alexander / Reiser, Jochen

Kidney international

2023 Volume 103, Issue 6, Page(s) 1056–1062

Abstract: Transient receptor potential canonical channels (TRPCs) are non-selective cationic channels that play a role in signal transduction, especially in G -protein-mediated signaling cascades. TRPC5 is expressed predominantly in the brain but also in the ... ...

Abstract	Transient receptor potential canonical channels (TRPCs) are non-selective cationic channels that play a role in signal transduction, especially in G -protein-mediated signaling cascades. TRPC5 is expressed predominantly in the brain but also in the kidney. However, its role in kidney physiology and pathophysiology is controversial. Some studies have suggested that TRPC5 drives podocyte injury and proteinuria, particularly after small GTPase Rac1 activation to induce the trafficking of TRPC5 to the plasma membrane. Other studies using TRPC5 gain-of-function transgenic mice have questioned the pathogenic role of TRPC5 in podocytes. Here, we show that TRPC5 over-expression or inhibition does not ameliorate proteinuria induced by the expression of constitutively active Rac1 in podocytes. Additionally, single-cell patch-clamp studies did not detect functional TRPC5 channels in primary cultures of podocytes. Thus, we conclude that TRPC5 plays a role redundant to that of TRPC6 in podocytes and is unlikely to be a useful therapeutic target for podocytopathies.
MeSH term(s)	Mice ; Animals ; Podocytes/pathology ; TRPC Cation Channels/genetics ; TRPC Cation Channels/metabolism ; Glomerulosclerosis, Focal Segmental/pathology ; Monomeric GTP-Binding Proteins/metabolism ; TRPC6 Cation Channel/genetics ; TRPC6 Cation Channel/metabolism ; Proteinuria/pathology ; Mice, Transgenic ; Transcription Factors/metabolism
Chemical Substances	TRPC Cation Channels ; Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; TRPC6 Cation Channel ; Transcription Factors ; Trpc5 protein, mouse
Language	English
Publishing date	2023-02-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2023.01.016
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