Cathepsin C is a novel mediator of podocyte and renal injury induced by hyperglycemia

Irena Audzeyenka , Patrycja Rachubik , Dorota Rogacka , Marlena Typiak , Tomasz Kulesza , Stefan Angielski , Michał Rychłowski , Magdalena Wysocka , Natalia Gruba , Adam Lesner , Moin A. Saleem , Agnieszka Piwkowska

Abstract

A growing body of evidence suggests a role of proteolytic enzymes in the development of diabetic nephropathy. Cathepsin C (CatC) is a well-known regulator of inflammatory responses, but its involvement in podocyte and renal injury remains obscure. We used Zucker rats, a genetic model of metabolic syndrome and insulin resistance, to determine the presence, quantity, and activity of CatC in the urine. In addition to the animal study, we used two cellular models, immortalized human podocytes and primary rat podocytes, to determine mRNA and protein expression levels via RT-PCR, Western blot, and confocal microscopy, and to evaluate CatC activity. The role of CatC was analyzed in CatC-depleted podocytes using siRNA and glycolytic flux parameters were obtained from extracellular acidification rate (ECAR) measurements. In functional analyses, podocyte and glomerular permeability to albumin was determined. We found that podocytes express and secrete CatC, and a hyperglycemic environment increases CatC levels and activity. Both high glucose and non-specific activator of CatC phorbol 12-myristate 13-acetate (PMA) diminished nephrin, cofilin, and GLUT4 levels and induced cytoskeletal rearrangements, increasing albumin permeability in podocytes. These negative effects were completely reversed in CatC-depleted podocytes. Moreover, PMA, but not high glucose, increased glycolytic flux in podocytes. Finally, we demonstrated that CatC expression and activity are increased in the urine of diabetic Zucker rats. We propose a novel mechanism of podocyte injury in diabetes, providing deeper insight into the role of CatC in podocyte biology.
Publication typeIn press (online first, early view)
Author Irena Audzeyenka (FCh/DMBt) - [Polish Academy of Science]
Irena Audzeyenka,,
- Department of Molecular Biotechnology
- Polska Akademia Nauk
, Patrycja Rachubik
Patrycja Rachubik,,
-
, Dorota Rogacka (FCh/DMBt) - [Polish Academy of Science]
Dorota Rogacka,,
- Department of Molecular Biotechnology
- Polska Akademia Nauk
, Marlena Typiak
Marlena Typiak,,
-
, Tomasz Kulesza
Tomasz Kulesza,,
-
, Stefan Angielski
Stefan Angielski,,
-
, Michał Rychłowski (IFB/IB/LVMB)
Michał Rychłowski,,
- Laboratory of Virus Molecular Biology
, Magdalena Wysocka (FCh/DBCh/LMCh)
Magdalena Wysocka,,
- Laboratory of Medical Chemistry
, Natalia Gruba (FCh/DET/LBAN)
Natalia Gruba,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
, Adam Lesner (FCh/DET/LBAN)
Adam Lesner,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
et al.`
Journal seriesBiochimica et Biophysica Acta-Molecular Cell Research, [Biochimica et Biophysica Acta - Molecular Cell Research], ISSN 0167-4889, (N/A 140 pkt)
Issue year2020
Noonline first
Keywords in EnglishAlbumin permeability, cathepsin C, diabetic nephropathy, hyperglycemia, podocytes
ASJC Classification1307 Cell Biology; 1312 Molecular Biology
DOIDOI:10.1016/j.bbamcr.2020.118723
URL https://doi.org/10.1016/j.bbamcr.2020.118723
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)140
Score sourcejournalList
ScoreMinisterial score = 140.0, 20-04-2020, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.168; WoS Impact Factor: 2018 = 4.739 (2) - 2018=5.281 (5)
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