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Kidney Week

Abstract: FR-PO585

Dissecting Heterogeneity and Common Pathogenetic Pathways in Autosomal Dominant Tubulointerstitial Kidney Disease due to Mutations in REN

Session Information

Category: Genetic Diseases of the Kidneys

  • 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Schaeffer, Celine, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • De Fusco, Maurizio, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Pasqualetto, Elena, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Scolari, Caterina, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Izzi, Claudia, Universita degli Studi di Brescia, Brescia, Lombardia, Italy
  • Scolari, Francesco, Universita degli Studi di Brescia, Brescia, Lombardia, Italy
  • Rampoldi, Luca, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy

Group or Team Name

  • Molecular Genetics of Renal Disorders.
Background

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is a rare genetic disorder characterised by renal tubulointerstitial fibrosis and progressive chronic kidney disease. ADTKD is caused by mutations in different genes including REN encoding renin, a key player in the regulation of salt and blood pressure homeostasis. Renin is a secreted protein composed of 3 domains: the leader peptide allowing its insertion in the endoplasmic reticulum (ER), a pro-segment regulating its aspartyl protease activity, and the mature part. Mutations in mature renin lead to ER retention of mutant protein and to a late onset disease, while mutations in the leader peptide, associated with defective ER translocation, and mutations in the pro-segment, accumulating in the ER-to-Golgi compartment, lead to early onset disease.

Methods

We used transiently and stably transfected cells as well as an inducible system of renin expression to investigate the effect of mutations on renin trafficking.

Results

We demonstrated an unprecedented effect of mutations in the leader peptide and pro-segment leading to full or partial mistargeting of mutated protein to mitochondria. By studying GFP-fusion constructs we observed that the pre-pro sequence of renin, carrying mutation in either the leader peptide or the pro-segment, is necessary and sufficient to drive mitochondrial rerouting. In turn, this leads to mitochondrial import defect and mitochondria fragmentation. Induction of the 3 branches of the Unfolded Protein Response is observed in cells expressing renin mutated in the mature part, while induction of the IRE1 branch only is observed for the other mutants. Interestingly, the chronic expression of all mutants leads to toxicity and cell death.

Conclusion

Our results unravel a common cellular phenotype for mutants in the leader peptide and pro-segment (i.e. mitochondrial mistargeting) associated with an early-onset disease that differs from the one associated with mutants in the mature part (i.e. ER retention) that lead to a late onset disease. We currently aim at understanding how expression of these different mutants eventually converges to kidney inflammation and fibrosis by characterising stress signals emerging from the ER and mitochondria.

Funding

  • Private Foundation Support