Kidney Week

Abstract: PO1688

The Calcium-Sensing Receptor Restores Podocyte Function in Proteinuric Humans and Mice

Session Information

• Podocyte Pathobiology: Basic Science Studies and Animal Models
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Muehlig, Anne Katrin, Department of Pediatric Nephrology, University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Anne Katrin Muehlig, MD

• Steingroever, Johanna, Department of Pediatric Nephrology, University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Johanna Steingroever,

• Sachs, Wiebke, Center of Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Wiebke Sachs,

• Meyer-Schwesinger, Catherine, Center of Experimental Medicine, Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Catherine Meyer-Schwesinger,

• Choi, Hoon Young, Yonsei University College of Medicine Department of Internal Medicine, Seoul, Korea (the Republic of)

Hoon Young Choi,

• Endlich, Nicole, Department of Anatomy and Cell Biology, University of Greifswald, Greifswald, Germany

Nicole Endlich,

• Braun, Fabian, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Fabian Braun,

• Huber, Tobias B., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Tobias B. Huber,

• Puelles, Victor G., III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Victor G. Puelles,

• Schmitt, Claus Peter, Department of Pediatrics, Heidelberg University Hospital, Heidelberg, Germany

Claus Peter Schmitt,

• Oh, Jun, Department of Pediatric Nephrology, University Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Jun Oh,

Background

Calcimimetic agents allosterically increase the calcium (Ca²⁺) sensitivity of the calcium-sensing receptor (CaSR), which suppresses the secretion of parathormone in the parathyroid gland and therefore regulates Ca²⁺-homeostasis. The CaSR is furthermore expressed in the tubular system and to a lesser extend in podocytes. Activation of CaSR reduces glomerular proteinuria and podocyte damage in animals. However, the precise role of the podocyte CaSR is still unclear.

Methods

A CaSR knockdown (KD) in murine podocytes and podocyte-specific CaSR knockout (KO) in BALB/c mice were generated to study its role in proteinuria.

Results

Podocyte CaSR KD abolished the calcimimetic R-568 mediated Ca²⁺-influx, reduced the number of actin fibers, cellular attachment and migration velocity in podocytes. In contrast, the activation of the CaSR with R-568 protected the wildtype cells from Adriamycin (ADR)-induced cytoskeletal rearrangement and reduction in adhesion capacity. In vivo ADR-induced proteinuria enhanced glomerular CaSR expression in wild type mice (control vs ADR: 33.5±2.0 vs 75.8±7.8 CaSR positive podocytes (%); p=0.0286). In podocyte-specific CaSR KO ADR treatment resulted in a higher albuminuria (control vs KO: 27.9±38.1 vs 85.9±52.7 g/galbumin/creatinine; p=0.023 at day 7), podocyte foot process effacement, podocyte loss (control vs KO: 3504±283.1 vs 2969±547.2 p57+cells/mm²; p=0.0238 at day 8) and glomerular sclerosis compared to wild type littermates. In addition, four children with nephrotic syndrome, objecting glucocorticoid therapy, were treated with the calcimimetic cinacalcet for 1 to 33 days. Proteinuria declined transiently by up to 96 %, serum albumin increased and edema resolved.

Conclusion

The activation of CaSR regulates key podocyte functions and protects from ADR induced cellular damage in vitro. The CaSR reduces toxin induced proteinuria, podocyte loss and glomerular damage in mice. Our findings suggest a major role of CaSR signaling in glomerular disease.