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Abstract: FR-PO954

CaSR Activation Corrects the Impaired Mitochondrial Energy Status in Human Cell Models of ADPKD

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Di Mise, Annarita, University of Bari, Bari, Italy
  • Ranieri, Marianna, University of Bari, Bari, Italy
  • Centrone, Mariangela, University of Bari, Bari, Italy
  • Venneri, Maria, University of Bari, Bari, Italy
  • Tamma, Grazia, University of Bari, Bari, Italy
  • Valenti, Daniela, Institute of Biomembranes, Bioenergetics and Molecular Biotechonologies, Bari, Italy
  • Valenti, Giovanna, University of Bari, Bari, Italy

Clinical and fundamental research data suggest that reduced resting cytosolic calcium (Ca2+) concentration and increased level of cAMP are two of the most proximal events in the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Reduced cellular free Ca2+ found in ADPKD, can on the other hand affect mitochondrial function and ATP production and, interestingly, a relationship between mitochondria and renal polycystic diseases have been suggested. CaSR is a G protein coupled receptor, which plays an essential role in regulating Ca2+ homeostasis whose activation is associated with an increase in intracellular Ca2+ and decrease in cAMP. We have recently reported (Di Mise et al, Sci Rep, 2018) that selective CaSR activation reduces intracellular cAMP and mTOR, and increases intracellular Ca2+, reversing the principal ADPKD dysregulations. Here, the effect of CaSR activation on mitochondrial energy status is investigated.


Control human conditionally immortalized Proximal Tubular Epithelial cells with stably down-regulated PKD1 (ciPTEC-PC1KD) were used as experimental tools.


The investigation of the bioenergetics status in ciPTEC-PC1KD revealed a multilevel inhibition of the mitochondrial ATP production by oxidative phosphorylation (OXPHOS) in ciPTEC-PC1KD compared with wt cells, specifically at complex I, complex II and complex IV levels. Interestingly, ciPTEC-PC1KD have significantly lower mitochondrial Ca2+ levels (88.05 2.6%), associated with a severe deficit in mitochondrial ATP production (38 ± 4%), with respect to wt cells, secondary to the OXPHOS impairment. Notably, selective CaSR activation with the calcimimetic NPS-R568 increases mitochondrial Ca2+ content close to the levels found in resting wt cells, and fully recovers the cell energy deficit associated to the PC1 silencing.


Together these data indicate that, besides reversing altered intracellular Ca2+, cAMP and mTOR, selective CaSR activation in PKD1 deficient cells corrects mitochondrial energy status that, in ADPKD, is known to facilitate cyst formation. These findings identify CaSR as a potential therapeutic target.


  • Government Support - Non-U.S.