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Kidney Week

Abstract: TH-PO478

Exploring the Molecular Basis of Ramipril-Induced Nephroprotection in Alport Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Yamamura, Tomohiko, Wellcome Trust Centre for Cell Matrix Research, Manchester, Manchester, United Kingdom
  • Williams, Emily, Wellcome Trust Centre for Cell Matrix Research, Manchester, Manchester, United Kingdom
  • Morais, Mychel R P T, Wellcome Trust Centre for Cell Matrix Research, Manchester, Manchester, United Kingdom
  • Lennon, Rachel, Wellcome Trust Centre for Cell Matrix Research, Manchester, Manchester, United Kingdom
Background

Renin-angiotensin system inhibitors such as angiotensin-converting enzyme Inhibitors (ACEi) play a central role in the treatment of CKD, and they are known to reduce proteinuria and extend kidney survival in Alport syndrome. This beneficial effect has been explained by the reduction of intraglomerular pressure and the inhibition of inflammation and subsequent fibrosis. However, the actual molecular changes induced by ACEi in the kidneys are yet elucidated.

Methods

The ACEi ramipril was administered orally (n=10 each) to a mouse model of Alport syndrome (Col4a5 knockout). Treatment was initiated at five weeks (early treatment group) or ten weeks (late treatment group) and continued until 16 weeks of age, with comprehensive evaluation including functional studies, imaging and mass spectrometry-based proteomic analysis kidney tissue.

Results

The mean urinary albumin-creatinine ratio ± SEM was significantly lower (p<0.01) in both the early treatment group (1417±470.3) and the late treatment group (2984±1116) compared to the no-treatment group (8902±1320). No significant differences were observed between the early and late treatment groups. Although serum BUN was not significantly different between the no-treatment and treatment groups, light microscopy showed that the early-treatment group had less cellular infiltration of the interstitial area than the no-treatment and the late-treatment group. Proteomic analysis revealed distinct proteomic profiles not only between Alport mice and wild-type mice but also between ACEi-treated Alport mice and non-treated Alport mice. With pathway enrichment analysis, we found significant enrichment for terms associated with chaperonin-mediated protein folding, extracellular matrix organisation and glycosaminoglycan metabolism in ACEi-treated mice compared to untreated mice.

Conclusion

The present study indicates that the molecular mechanisms of the nephroprotective effects of ACEi, such as the reduction of proteinuria and improved histological findings in the Alport mouse, involve proteins related to chaperonin-mediated protein folding, extracellular matrix organisation and glycosaminoglycan metabolism pathways in the kidney.