Subtitle:

The role of phosphate transporters in the development of glomerular clacification and in the induction of insulin resistance in podocytes

Institutional creator:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Contributor:

Piwkowska, Agnieszka (Promotor)

Place of publishing:

Warszawa

Degree name:

doktor

Level of degree:

2

Degree discipline :

medical sciences

Degree grantor:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Type of object:

Praca dyplomowa

Abstract:

Podocytes are specialized cells of the visceral epithelium, which, together with the glomerular capillary endothelium and the basement membrane, form a unique structure – the glomerular filtration barrier (GFB). In the morphology of the podocyte, foot processes can be distinguished, which, by interlocking with each other, form slit diaphragms (SD) – highly dynamic, and thus the most sensitive to damage, elements of the GFB. It is SD that prevents macromolecules from entering the ultrafiltrate. Podocytes are also insulin sensitive, and alterations in the homeostasis of this hormone affect their physiology. Diabetic kidney disease (DKD), is an example of the most common disorder leading to podocyte injury. Chronic hyperinsulinemia and hyperglycemia present in the course of DKD cause insulin resistance of podocytes and progressive disintegration of GFB, which leads to albuminuria. GFB damage is often overlooked in the initial stages of the disease due to its oligosymptomatic manifestation. Soft tissues calcification is a deleterious complication of diabetes. Due to dysregulated hormonal balance and abnormal kidney function, phosphate ions (Pi) are retained in the body. Long-lasting hyperphosphatemia favors the deposition of calcium phosphate salts in organs where this process does not occur under physiological conditions. So far, scientists have most accurately described the pathomechanism of vascular calcification (VC). From these studies it is known that mechanism of VC involves the significant participation of sodium-dependent phosphate transporters (NaPi 2c, Pit 1, Pit 2), whose function is the transport of Pi into the cell, and the XPR1, which exports Pi from the cell. Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) also participates in maintaining phosphate homeostasis, mainly by generation of pyrophosphate (PPi) – the strongest inhibitor of calcification. Both NPP1 and Pit 1 are also regulators of intracellular insulin signaling. The aim of the research was to determine the influence of the diabetic environment on phosphate homeostasis in podocytes. In particular, the role of Pi transport system in the development of glomerular calcification and the formation of insulin resistance of podocytes was investigated. In the first part of the study, it was established that high glucose (HG) concentration leads to changes in the amount and cellular location of the analyzed phosphate transporters. In the cell membrane of the podocyte, the amount of sodium-dependent Pi transporters decreased, while the translocation of XPR1 to the plasma membrane elevated. In addition, membrane exposure of NPP1 was also reduced, resulting in attenuated production of PPi in the extracellular space (ES). The above-mentioned observations suggest that under HG conditions, the calcification processes are intensified due to the retention of Pi ions in ES and the reduction of the efficiency of natural mineralization inhibitors. Next, the role of Pit 1 and NPP1 proteins in insulin signaling in the podocyte was determined. It was discovered for the first time that complexes of the NPP1 enzyme with both the Pit 1 transporter and the insulin receptor (IR) are formed in insulin resistant podocytes. In addition, silencing of the SLC20A1 gene encoding the Pit 1 protein led to the insensitivity of podocytes to insulin, which was manifested by inhibition of glucose uptake and internalization of IR and insulin-dependent glucose transporter type 4 (GLUT 4). This indicates that Pit 1 protein, besides its role as the Pi transporter, is a key factor determining the sensitivity of podocytes to insulin. The above-mentioned findings allow for a better understanding of the mechanism of podocyte damage in the course of DKD and may contribute to the development of more efficient diagnostic and therapeutic tools. The newly discovered mechanisms in the long run may significantly improve the quality of life of people suffering from diabetes and its complications.

Detailed Resource Type:

PhD Dissertations

Format:

pdf

Resource Identifier:

oai:rcin.org.pl:240198

Source:

IMDiK PAN, sygn. ZS 434 ; click here to follow the link

Language:

pol

Language of abstract:

eng

Rights:

Creative Commons Attribution BY 4.0 license

Terms of use:

Copyright-protected material. [CC BY 4.0] May be used within the scope specified in Creative Commons Attribution BY 4.0 license, full text available at: ; -

Digitizing institution:

Mossakowski Medical Research Institute PAS

Original in:

Library of the Mossakowski Medical Research Institute PAS

Projects co-financed by:

Operational Program Digital Poland, 2014-2020, Measure 2.3: Digital accessibility and usefulness of public sector information; funds from the European Regional Development Fund and national co-financing from the state budget.

Access:

Open