Cathepsin C is a novel mediator of podocyte and renal injury induced by hyperglycemia
| Autor: | Dorota Rogacka, Natalia Gruba, Stefan Angielski, Tomasz Kulesza, Adam Lesner, Marlena Typiak, Magdalena Wysocka, Michał Rychłowski, Moin A. Saleem, Patrycja Rachubik, Agnieszka Piwkowska, Irena Audzeyenka |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Kidney albumin permeability Cathepsin C Permeability Podocyte Nephrin Diabetic nephropathy 03 medical and health sciences 0302 clinical medicine Western blot Genetic model medicine Animals Humans Diabetic Nephropathies Obesity RNA Messenger Molecular Biology Serum Albumin Metabolic Syndrome biology medicine.diagnostic_test Chemistry Podocytes diabetic nephropathy Proteolytic enzymes Membrane Proteins Cell Biology medicine.disease Cell biology Rats Rats Zucker Disease Models Animal 030104 developmental biology medicine.anatomical_structure podocytes Glucose 030220 oncology & carcinogenesis Gene Knockdown Techniques Hyperglycemia biology.protein Female hyperglycemia Insulin Resistance Transcriptome GLUT4 |
| Zdroj: | Audzeyenka, I, Rachubik, P, Rogacka, D, Typiak, M, Kulesza, T, Angielski, S, Rychłowski, M, Wysocka, M, Gruba, N, Lesner, A, Saleem, M A & Piwkowska, A 2020, ' Cathepsin C is a novel mediator of podocyte and renal injury induced by hyperglycemia ', Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, vol. 1867, no. 8, 118723 . https://doi.org/10.1016/j.bbamcr.2020.118723 |
| ISSN: | 1879-2596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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