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Abstract: FR-PO775

Low Nephron Number Resulting from SIRT3 Deficiency Increases Susceptibility to Renal Dysfunction Later in Life

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Morigi, Marina, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Pezzotta, Anna, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Perico, Luca, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Corna, Daniela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Benedetti, Valentina, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Brizi, Valerio, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Conti, Sara, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Sangalli, Fabio, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Rottoli, Daniela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Trionfini, Piera, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Xinaris, Christodoulos, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Perico, Norberto, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Zoja, Carlamaria, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Remuzzi, Giuseppe, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Benigni, Ariela, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
  • Imberti, Barbara, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
Background

Low nephron endowment is a risk factor for chronic kidney diseases (CKD) in adulthood but no causal correlation has been formally proved. We have demonstrated that mice lacking the mitochondrial protein Sirtuin 3 (SIRT3) are more susceptible to acute kidney injury than wild type (WT) mice. Here, we explored whether Sirt3-/- mice can be used as a low nephron number model and are more susceptible to CKD.

Methods

Metanephroi were isolated from WT and Sirt3-/- mice to study nephrogenesis. The susceptibility of Sirt3-/-mice to CKD was studied in adriamycin (ADR)- or bovine serum albumin (BSA)- induced progressive nephropathies.

Results

We demonstrated that, at the embryonic day 12.5, Sirt3-/- mice had less ureteric bud branching and fewer metanephric SIX2+ progenitor cells. Impaired nephrogenesis in Sirt3-/- mice resulted in a nephron deficit compared to WT mice (40% reduction at post-natal day 7, P<0.001), due to altered mitochondrial dynamics, biogenesis, mitophagy and energetic metabolism. Notably, low nephron endowment at birth is not enough to cause renal disease in adulthood, but enhances the susceptibility of Sirt3-/- mice to renal damage. Specifically, when Sirt3-/- mice were exposed to ADR or BSA overload, they experienced more severe proteinuria, podocyte loss (% reduction in WT-1+ cell density: Sirt3-/-, 68% vs WT, 30%, P<0.01) and vascular rarefaction than WT mice (% reduction in MECA-32+ cell density: Sirt3-/-, 57% and WT, 43%, P<0.05). We also proved that nephron deficit can be corrected through prenatal SIRT3 boosting. Indeed, in a model of low nephron number and reduced renal SIRT3 levels – WT mice born to mothers fed a low protein diet – nephron number was restored through NAD+ precursor nicotinamide riboside (NR) treatment.

Conclusion

Our results provide evidence that low nephron endowment is a critical determinant of susceptibility to CKD when the kidney is challenged by additional hits, and support the use of SIRT3 boosting during nephrogenesis as a therapeutic option for increasing nephron number.

Funding

  • Private Foundation Support