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Article: Metformin Protects against Podocyte Injury in Diabetic Kidney Disease.

Lehtonen, Sanna

2020 Volume 13, Issue 12

Abstract: Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it ... ...

Abstract	Metformin is the most commonly prescribed drug for treating type 2 diabetes mellitus (T2D). Its mechanisms of action have been under extensive investigation, revealing that it has multiple cellular targets, either direct or indirect ones, via which it regulates numerous cellular pathways. Diabetic kidney disease (DKD), the serious complication of T2D, develops in up to 50% of the individuals with T2D. Various mechanisms contribute to the development of DKD, including hyperglycaemia, dyslipidemia, oxidative stress, chronic low-grade inflammation, altered autophagic activity and insulin resistance, among others. Metformin has been shown to affect these pathways, and thus, it could slow down or prevent the progression of DKD. Despite several animal studies demonstrating the renoprotective effects of metformin, there is no concrete evidence in clinical settings. This review summarizes the renoprotective effects of metformin in experimental settings. Special emphasis is on the effects of metformin on podocytes, the glomerular epithelial cells that are central in maintaining the glomerular ultrafiltration function.
Language	English
Publishing date	2020-12-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph13120452
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: SHIPping out diabetes-Metformin, an old friend among new SHIP2 inhibitors.

Lehtonen, Sanna

Acta physiologica (Oxford, England)

2019 Volume 228, Issue 1, Page(s) e13349

Abstract: SHIP2 (Src homology 2 domain-containing inositol 5'-phosphatase 2) belongs to the family of 5'-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5'-position of PtdIns(3,4,5)P3 to ... ...

Abstract	SHIP2 (Src homology 2 domain-containing inositol 5'-phosphatase 2) belongs to the family of 5'-phosphatases. It regulates the phosphoinositide 3-kinase (PI3K)-mediated insulin signalling cascade by dephosphorylating the 5'-position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first-line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.
MeSH term(s)	Diabetes Mellitus, Type 2/drug therapy ; Diabetic Nephropathies ; Glomerular Filtration Barrier ; Humans ; Hypoglycemic Agents/therapeutic use ; Metformin/pharmacology ; Metformin/therapeutic use ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/antagonists & inhibitors
Chemical Substances	Hypoglycemic Agents ; Metformin (9100L32L2N) ; INPPL1 protein, human (EC 3.1.3.86) ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (EC 3.1.3.86)
Language	English
Publishing date	2019-08-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2218636-0
ISSN	1748-1716 ; 1748-1708
ISSN (online)	1748-1716
ISSN	1748-1708
DOI	10.1111/apha.13349
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Article ; Online: PACSIN proteins in vivo: Roles in development and physiology.

Dumont, Vincent / Lehtonen, Sanna

Acta physiologica (Oxford, England)

2022 Volume 234, Issue 3, Page(s) e13783

Abstract: Protein kinase C and casein kinase substrate in neurons (PACSINs), or syndapins (synaptic dynamin-associated proteins), are a family of proteins involved in the regulation of cell cytoskeleton, intracellular trafficking and signalling. Over the last ... ...

Abstract	Protein kinase C and casein kinase substrate in neurons (PACSINs), or syndapins (synaptic dynamin-associated proteins), are a family of proteins involved in the regulation of cell cytoskeleton, intracellular trafficking and signalling. Over the last twenty years, PACSINs have been mostly studied in the in vitro and ex vivo settings, and only in the last decade reports on their function in vivo have emerged. We first summarize the identification, structure and cellular functions of PACSINs, and then focus on the relevance of PACSINs in vivo. During development in various model organisms, PACSINs participate in diverse processes, such as neural crest cell development, gastrulation, laterality development and neuromuscular junction formation. In mouse, PACSIN2 regulates angiogenesis during retinal development and in human, PACSIN2 associates with monosomy and embryonic implantation. In adulthood, PACSIN1 has been extensively studied in the brain and shown to regulate neuromorphogenesis, receptor trafficking and synaptic plasticity. Several genetic studies suggest a role for PACSIN1 in the development of schizophrenia, which is also supported by the phenotype of mice depleted of PACSIN1. PACSIN2 plays an essential role in the maintenance of intestinal homeostasis and participates in kidney repair processes after injury. PACSIN3 is abundant in muscle tissue and necessary for caveolar biogenesis to create membrane reservoirs, thus controlling muscle function, and has been linked to certain genetic muscular disorders. The above examples illustrate the importance of PACSINs in diverse physiological or tissue repair processes in various organs, and associations to diseases when their functions are disturbed.
MeSH term(s)	Adaptor Proteins, Signal Transducing/physiology ; Animals ; Carrier Proteins/physiology ; Cytoskeletal Proteins/physiology ; Cytoskeleton/physiology ; Mice ; Neurons/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Cytoskeletal Proteins ; Pacsin2 protein, mouse
Language	English
Publishing date	2022-01-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2218636-0
ISSN	1748-1716 ; 1748-1708
ISSN (online)	1748-1716
ISSN	1748-1708
DOI	10.1111/apha.13783
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Article: Editorial: Podocyte Pathology and Nephropathy-An Update.

Lehtonen, Sanna / Lewko, Barbara

Frontiers in endocrinology

2019 Volume 10, Page(s) 528

Language	English
Publishing date	2019-07-30
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2019.00528
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Article: Glucose Transporters in Diabetic Kidney Disease-Friends or Foes?

Wasik, Anita A / Lehtonen, Sanna

Frontiers in endocrinology

2018 Volume 9, Page(s) 155

Abstract: Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin ... ...

Abstract	Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin resistance correlates with the development of albuminuria in non-diabetic and diabetic patients. There is also accumulating evidence that glomerular epithelial cells or podocytes are insulin sensitive and that insulin signaling in podocytes is essential for maintaining normal kidney function. At the cellular level, the mechanisms leading to the development of insulin resistance include mutations in the insulin receptor gene, impairments in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, or perturbations in the trafficking of glucose transporters (GLUTs), which mediate the uptake of glucose into cells. Podocytes express several GLUTs, including GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. Of these, the most studied ones are GLUT1 and GLUT4, both shown to be insulin responsive in podocytes. In the basal state, GLUT4 is preferentially located in perinuclear and cytosolic vesicular structures and to a lesser extent at the plasma membrane. After insulin stimulation, GLUT4 is sorted into GLUT4-containing vesicles (GCVs) that translocate to the plasma membrane. GCV trafficking consists of several steps, including approaching of the GCVs to the plasma membrane, tethering, and docking, after which the lipid bilayers of the GCVs and the plasma membrane fuse, delivering GLUT4 to the cell surface for glucose uptake into the cell. Studies have revealed novel molecular regulators of the GLUT trafficking in podocytes and unraveled unexpected roles for GLUT1 and GLUT4 in the development of DKD, summarized in this review. These findings pave the way for better understanding of the mechanistic pathways associated with the development and progression of DKD and aid in the development of new treatments for this devastating disease.
Language	English
Publishing date	2018
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2018.00155
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Article ; Online: Transcriptomic Profiling the Effects of Airway Exposure of Zinc Oxide and Silver Nanoparticles in Mouse Lungs.

Zhao, Lan / Wang, Shuyuan / Ilves, Marit / Lehtonen, Sanna / Saikko, Leena / El-Nezami, Hani / Alenius, Harri / Karisola, Piia

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: Consumers and manufacturers are exposed to nanosized zinc oxide (nZnO) and silver particles (nAg) via airways, but their biological effects are still not fully elucidated. To understand the immune effects, we exposed mice to 2, 10, or 50 μg of nZnO or ... ...

Abstract	Consumers and manufacturers are exposed to nanosized zinc oxide (nZnO) and silver particles (nAg) via airways, but their biological effects are still not fully elucidated. To understand the immune effects, we exposed mice to 2, 10, or 50 μg of nZnO or nAg by oropharyngeal aspiration and analyzed the global gene expression profiles and immunopathological changes in the lungs after 1, 7, or 28 days. Our results show that the kinetics of responses varied in the lungs. Exposure to nZnO resulted in the highest accumulation of F4/80- and CD3-positive cells, and the largest number of differentially expressed genes (DEGs) were identified after day 1, while exposure to nAg caused peak responses at day 7. Additionally, nZnO mainly activated the innate immune responses leading to acute inflammation, whereas the nAg activated both innate and adaptive immune pathways, with long-lasting effects. This kinetic-profiling study provides an important data source to understand the cellular and molecular processes underlying nZnO- and nAg-induced transcriptomic changes, which lead to the characterization of the corresponding biological and toxicological effects of nZnO and nAg in the lungs. These findings could improve science-based hazard and risk assessment and the development of safe applications of engineered nanomaterials (ENMs), e.g., in biomedical applications.
MeSH term(s)	Mice ; Animals ; Zinc Oxide/toxicity ; Metal Nanoparticles/toxicity ; Silver/toxicity ; Transcriptome ; Lung ; Nanoparticles
Chemical Substances	Zinc Oxide (SOI2LOH54Z) ; Silver (3M4G523W1G)
Language	English
Publishing date	2023-03-08
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/ijms24065183
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Article ; Online: Septins in kidney: A territory little explored.

Wasik, Anita A / Dash, Surjya N / Lehtonen, Sanna

Cytoskeleton (Hoboken, N.J.)

2018 Volume 76, Issue 1, Page(s) 154–162

Abstract: Septins are a conserved family of GTP-binding proteins that assemble into cytoskeletal filaments to function in a highly sophisticated and physiologically regulated manner. Originally septins were discovered in the budding yeast as membrane-associated ... ...

Abstract	Septins are a conserved family of GTP-binding proteins that assemble into cytoskeletal filaments to function in a highly sophisticated and physiologically regulated manner. Originally septins were discovered in the budding yeast as membrane-associated filaments that affect cell polarity and cytokinesis. In the last decades, much progress has been made in understanding the biochemical properties and cell biological functions of septins. In line with this, mammalian septins have been shown to be involved in various cellular processes, including regulation of cell polarity, cytoskeletal organization, vesicle trafficking, ciliogenesis, and cell-pathogen interactions. A growing number of studies have shown that septins play important roles in tissue and organ development and physiology; yet, little is known about their role in the kidney. In the following review, we discuss the structure and functions of septins in general and summarize the evidence for their presence and roles in the kidney.
MeSH term(s)	Animals ; Cell Movement/genetics ; Cell Movement/physiology ; Cell Polarity/genetics ; Cell Polarity/physiology ; Cytokinesis/genetics ; Cytokinesis/physiology ; Kidney/metabolism ; Septins/genetics ; Septins/metabolism
Chemical Substances	Septins (EC 3.6.1.-)
Language	English
Publishing date	2018-08-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2534372-5
ISSN	1949-3592 ; 1949-3584
ISSN (online)	1949-3592
ISSN	1949-3584
DOI	10.1002/cm.21477
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Article ; Online: Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity.

Cabrera, Luz E / Schmotz, Constanze / Saleem, Moin A / Lehtonen, Sanna / Vapalahti, Olli / Vaheri, Antti / Mäkelä, Satu / Mustonen, Jukka / Strandin, Tomas

Viruses

2022 Volume 14, Issue 3

Abstract: Old-world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular ... ...

Abstract	Old-world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus-caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS-associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus-infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus-infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.
MeSH term(s)	Acute Kidney Injury ; Endothelial Cells ; Glucuronidase ; Hemorrhagic Fever with Renal Syndrome/complications ; Humans ; Proteinuria/etiology ; Puumala virus ; Severity of Illness Index
Chemical Substances	heparanase (EC 3.2.1.-) ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2022-02-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v14030450
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Article ; Online: Nephrin Trafficking beyond the Kidney--Role in Glucose-Stimulated Insulin Secretion in β Cells.

Lehtonen, Sanna / Jalanko, Hannu

Journal of the American Society of Nephrology : JASN

2015 Volume 27, Issue 4, Page(s) 965–968

MeSH term(s)	Animals ; Female ; Humans ; Insulin/metabolism ; Insulin Secretion ; Male ; Membrane Proteins/physiology ; Receptor, Insulin/physiology ; Signal Transduction/physiology ; TOR Serine-Threonine Kinases/physiology
Chemical Substances	Insulin ; Membrane Proteins ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Receptor, Insulin (EC 2.7.10.1)
Language	English
Publishing date	2015-09-23
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2015080960
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Article: Increased Heparanase Levels in Urine during Acute Puumala Orthohantavirus Infection Are Associated with Disease Severity

Cabrera, Luz E. / Schmotz, Constanze / Saleem, Moin A. / Lehtonen, Sanna / Vapalahti, Olli / Vaheri, Antti / Mäkelä, Satu / Mustonen, Jukka / Strandin, Tomas

Viruses. 2022 Feb. 22, v. 14, no. 3

2022

Abstract: Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular ... ...

Abstract	Old–world orthohantaviruses cause hemorrhagic fever with renal syndrome (HFRS), characterized by acute kidney injury (AKI) with transient proteinuria. It seems plausible that proteinuria during acute HFRS is mediated by the disruption of the glomerular filtration barrier (GFB) due to vascular leakage, a hallmark of orthohantavirus–caused diseases. However, direct infection of endothelial cells by orthohantaviruses does not result in increased endothelial permeability, and alternative explanations for vascular leakage and diminished GFB function are necessary. Vascular integrity is partly dependent on an intact endothelial glycocalyx, which is susceptible to cleavage by heparanase (HPSE). To understand the role of glycocalyx degradation in HFRS–associated proteinuria, we investigated the levels of HPSE in urine and plasma during acute, convalescent and recovery stages of HFRS caused by Puumala orthohantavirus. HPSE levels in urine during acute HFRS were significantly increased and strongly associated with the severity of AKI and other markers of disease severity. Furthermore, increased expression of HPSE was detected in vitro in orthohantavirus–infected podocytes, which line the outer surfaces of glomerular capillaries. Taken together, these findings suggest the local activation of HPSE in the kidneys of orthohantavirus–infected patients with the potential to disrupt the endothelial glycocalyx, leading to increased protein leakage through the GFB, resulting in high amounts of proteinuria.
Keywords	Hantaviridae infections ; Puumala orthohantavirus ; acute kidney injury ; disease severity ; fever ; glomerular filtration rate ; permeability ; proteinuria ; urine
Language	English
Dates of publication	2022-0222
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v14030450
Database	NAL-Catalogue (AGRICOLA)

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