Angiotensin converting-enzyme inhibition restores glomerular glycosaminoglycans in rat puromycin nephrosis.

Abstract

BACKGROUND:

Aberrant glomerular polyanionic charge of glycosaminoglycans (GAGs) and sialic acid expression has been observed in proteinuric human and experimental glomerular diseases. Angiotensin-converting enzyme inhibitors (ACEI) lower proteinuria and amend renal function deterioration via hemodynamic mechanisms. We tested the hypothesis that ACEI modulate proteinuria additionally by modifying glomerular GAGs.

METHODS:

In this study, we explored the effects of the ACEI enalapril on proteinuria and GAG synthesis in puromycin aminonucleoside (PAN)-treated rats. We employed cationic colloidal gold (CCG) localization in glomerular basement membranes (GBM) to identify GAGs by electron microscopy and determined sialic acid residues by immunohistochemical staining with lectins. To clarify ACEI effects on GAG production in vitro, we studied de novo GAG synthesis into newly synthesized proteoglycans in podocytes and mesangial cells using 35S incorporation. Cells were incubated with or without PAN, and with increasing doses of the ACEI enalaprilat.

RESULTS:

PAN rats developed severe proteinuria that was significantly improved by enalapril treatment. In non-treated PAN rats GBM GAGs were reduced, whereas in the enalapril-treated group GBM GAGs were significantly increased to control levels. Enalapril did not affect glomerular sialic acid. Furthermore, in cultured podocytes and mesangial cells PAN decreased de novo GAG synthesis, an effect which was significantly ameliorated by enalaprilat treatment.

CONCLUSION:

Treatment with ACEI improves permselectivity properties of the glomerular capillary wall by maintaining its GAG content. This finding provides an additional new mechanism, whereby ACEI exert anti-proteinuric effects.

• Authors: Michal Herman-Edelstein, Avry Chagnac, Zvi Nevo, Ehud Skutelsky, Yoav Evron, Yehudit Hirsch, Lya Ben-Dor, Idit Schwartz, Doron Schwartz, Talia Weinstein
• Journal: Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (Exp Toxicol Pathol) Vol. 68 Issue 10 Pg. 543-552 (Nov 2016) ISSN: 1618-1433 [Electronic] Germany
• PMID: 27591087 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier GmbH. All rights reserved.

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Glycosaminoglycans
• Protein Synthesis Inhibitors
• Puromycin Aminonucleoside
• Enalapril

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology)
• Animals
• Disease Models, Animal
• Enalapril (pharmacology)
• Glycosaminoglycans (biosynthesis)
• Immunohistochemistry
• Kidney Glomerulus (drug effects, metabolism, ultrastructure)
• Male
• Microscopy, Electron, Transmission
• Nephrosis (metabolism, pathology)
• Podocytes (drug effects)
• Protein Synthesis Inhibitors (toxicity)
• Puromycin Aminonucleoside (toxicity)
• Rats
• Rats, Wistar