Kidney Week

Abstract: FR-PO570

The Direct Physical Interaction Between Calcium-Sensing Receptor and Polycystin-2: Implication in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Session Information

• Genetic Diseases: Cystic - Basic
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Di Mise, Annarita, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Annarita Di Mise,

• Venneri, Maria, Istituti Clinici Scientifici Maugeri SpA SB IRCCS, Pavia, Lombardia, Italy

Maria Venneri,

• Ferrulli, Angela, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Angela Ferrulli,

• Ranieri, Marianna, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Marianna Ranieri,

• Centrone, Mariangela, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Mariangela Centrone,

• Caroppo, Rosa, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Rosa Caroppo,

• Tamma, Grazia, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Grazia Tamma,

• Valenti, Giovanna, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Giovanna Valenti,

Background

ADPKD is a ciliopathy caused by mutations in PKD1 or PKD2 genes, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which form a complex localized to the primary cilium. PC2 is a member of the transient receptor potential polycystic (TRPP) family of cation channels acting as a non-selective cation channel which, in the primary cilium of renal epithelial cells, preferentially conducts K⁺ and Na⁺ over Ca²⁺ ions. In this study, we explored the possibility that the Calcium Sensing Receptor (CaSR) is involved in PC2 functional regulation.

Methods

Human conditionally immortalized Proximal Tubular Epithelial cells isolated from urine sediments (ciPTECwt) and with stably down-regulated PKD2 (ciPTEC-PC2KD), expressing endogenous CaSR, were used as experimental tools.

Results

Immunofluorescence experiments showed the expression of both CaSR and PC2 on the primary cilium. CaSR and PC2 co-immunoprecipitated both in ciPTEC and mouse kidney. Worthy of note, Proximity Ligation Assay demonstrated the direct interaction between CaSR and PC2 in both ciPTEC and mouse kidney slices. Preliminary electrophysiological measurements demonstrated that, in ciPTEC, CaSR activation caused plasma membrane hyperpolarization, consistent with modulation of cation channels. Interestingly, the membrane hyperpolarization induced by the activation of CaSR in ciPTEC-PC2KD was significantly lower with respect to ciPTECwt.

Conclusion

These studies underline the functional coupling of CaSR with PC2, providing a rationale for the amelioration of the principal cellular ADPKD dysregulations observed in our previous studies in ciPTEC-PC1KD exposed to calcimimetics (CaSR allosteric modulators) as well as in animal models of ADPKD.

Funding

• Government Support – Non-U.S.