Marc Wein, MD, PhDMarc Wein, MD, PhD, a physician-researcher in the Division of Endocrinology at Massachusetts General Hospital, is the senior author of an article in the Journal of Clinical Investigation, “A Parathyroid Hormone/Salt-Inducible Kinase Signaling Axis Controls Renal Vitamin D Activation and Organismal Calcium Homeostasis.”

What Question Were You Investigating with this Study?

It has long been appreciated that the kidney is the key organ responsible for the generation of the active form of vitamin D. However, the molecular steps involved in this signaling cascade have remained unknown. In this study, we sought to define how parathyroid hormone stimulates vitamin D activation in the kidney.

What Methods or Approach Did You Use?

To study how this signaling works, we used human kidney organoids, single-cell RNA-sequencing, mouse genetics, a chronic kidney disease model, and new pharmacologic agents.

What Did You Find?

We identified a key role for salt-inducible kinases in regulating vitamin D activation downstream of parathyroid hormone (PTH) action. We also defined the subset of cells within the proximal tubule where PTH triggers vitamin D activation.

What are the Implications?

The findings have major implications for chronic kidney disease where patients show defects in vitamin D activation. This work suggests that small molecule salt inducible kinase inhibitors might be useful therapeutic agents to stimulate vitamin D activation in the setting of chronic kidney disease. To test this idea, we are now testing this new therapeutic approach in preclinical models of chronic kidney disease and associated mineral/bone and vascular disorders.

Paper cited:

Yoon, S. H., Meyer, M. B., Arevalo Rivas, C., Tekguc, M., Zhang, C., Wang, J. S., Castro Andrade, C. D., Strauss, K. E., Sato, T., Benkusky, N., Lee, S. M., Berdeaux, R., Foretz, M., Sundberg, T. B., Xavier, R. J., Adelmann, C. H., Brooks, D. J., Anselmo, A., Sadreyev, R. I., Rosales, I. A., … Wein, M. N. (2023). A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis. The Journal of clinical investigation, e163627. Advance online publication.

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.