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

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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.

Original languageEnglish
Article number118723
JournalBiochimica et Biophysica Acta (BBA) - Molecular Cell Research
Volume1867
Issue number8
Early online date14 Apr 2020
DOIs
Publication statusPublished - 1 Aug 2020

Keywords

  • albumin permeability
  • Cathepsin C
  • diabetic nephropathy
  • hyperglycemia
  • podocytes

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