Cathepsin B increases ENaC activity leading to hypertension early in nephrotic syndrome
Autor: | Luis Zanon Rodriguez, Ursula Kern, Franziska Theilig, Ina Maria Schiessl, Jean Luc Magnin, Eileen Dahlke, Géraldine Mollet, Oliver Schilling, Alexey Larionov, Madlen Kunke, Hayo Castrop, Abdel A. Alli |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Epithelial sodium channel medicine.medical_specialty hypertension Nephrotic Syndrome Mice Transgenic Cathepsin B Podocyte Amiloride Mice 03 medical and health sciences 0302 clinical medicine Focal segmental glomerulosclerosis Internal medicine Epithelial Sodium Channel Blockers medicine Animals Epithelial Sodium Channels focal segmental glomerulosclerosis biology Glomerulosclerosis Focal Segmental Chemistry Sodium Intracellular Signaling Peptides and Proteins Membrane Proteins Original Articles Cell Biology medicine.disease Proteinuria Kidney Tubules 030104 developmental biology medicine.anatomical_structure Endocrinology 030220 oncology & carcinogenesis Proteolysis Slit diaphragm Podocin biology.protein epithelial sodium channel Molecular Medicine Original Article Lysosomes Nephrotic syndrome medicine.drug |
Zdroj: | Journal of Cellular and Molecular Medicine |
Popis: | The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria‐dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full‐length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+/K+‐ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified. |
Databáze: | OpenAIRE |
Externí odkaz: |