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

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• 作者：Michal Herman-Edelstein^a ; Avry Chagnac^a ; Zvi Nevo^b ; Ehud Skutelsky^c ; Yoav Evron^a ; Yehudit Hirsch^a ; Lya Ben-Dor^c ; Idit Schwartz^d ; Doron Schwartz^d ; Talia Weinstein^d ; ^{taliaw@tlvmc.gov.il" class="auth_mail" title="E-mail the corresponding author} ; ^{tweinste@post.tau.ac.il" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACEI ; angiotensin converting-enzyme inhibitors ; CCG ; cationic colloidal gold ; EM ; electron microscopy ; GAG ; glycosaminoglycan ; GBM ; glomerular basement membrane ; HS ; heparan sulfate ; HSPG ; heparan sulfate proteoglycans ; PAN ; puromycinaminonucleoside ; RAS ; renin-angiotensin system
• 刊名：Experimental and Toxicologic Pathology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：68
• 期：10
• 页码：543-552
• 全文大小：2758 K

文摘

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.