Kidney Week

Abstract: SA-PO226

Tissue-Specific Deletion of Cyp24a1 Reveals Independent Systemic and Intestinal Vitamin D Regulation in Mice

Session Information

• CKD-MBD: Basic and Translational
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Fuchs, Michaela A.A., Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Michaela A.A. Fuchs, PhD

• Grabner, Alexander, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Alexander Grabner, MD

• Shi, Melody, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Melody Shi, MD

• Murray, Susan Louise, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Susan Louise Murray, MD, MBChB

• Burke, Emily, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Emily Burke

• Latic, Nejla, Veterinarmedizinische Universitat Wien, Wien, Wien, Austria

Nejla Latic, PhD, DVM

• Thiriveedi, Venkataramana, Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Venkataramana Thiriveedi, APN

• Ide, Shintaro, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Shintaro Ide, MD, PhD

• Abe, Koki, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Koki Abe, MD, PhD

• Kitai, Hiroki, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Hiroki Kitai, MD, PhD

• Souma, Tomokazu, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Tomokazu Souma, MD, PhD

• Wolf, Myles, Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States

Myles Wolf, MD, MMSc

Background

Dysregulation of vitamin D, a central regulator of mineral metabolism, is a severe complication of chronic kidney disease (CKD), leading to hypocalcemia, secondary hyperparathyroidism and increased risk of fractures. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by the 1α-hydroxylase CYP27B1 in the kidney from its precursor, 25-dihydroxyvitamin D (25D). Catabolism of 1,25D is controlled by the expression of the 24-hydoxylase CYP24A1 in proximal tubules and other important Vitamin D target organs like the intestines or parathyroid glands. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in systemic regulation of mineral homeostasis, but little is known about its tissue-specific effects.

Methods

We used single cell RNA sequencing coupled with novel mouse models of tissue specific CYP24A1 deletion to address these questions.We analyzed the responses of mice with inducible global deletion, kidney-specific, and intestine-specific Cyp24a1 deletion to standard calcium diet, high calcium diet and 1,25D injection.

Results

Global and kidney-specific Cyp24a1 deletion caused similar phenotypes of systemic vitamin D intoxication: elevated circulating 1,25D and 25D levels, activation of vitamin D receptor target genes in the kidney and intestine, hypercalcemia, increased levels for fibroblast growth factor 23 and suppressed parathyroid hormone (PTH). In contrast, intestine-specific deletion of Cyp24a1 led to no changes in systemic levels of 1,25D or 25D, yet vitamin D receptor target genes were activated in the intestine, and PTH was suppressed in response to high calcium diet without detectable changes to serum calcium levels.

Conclusion

These results implicate a central role for renal CYP24A1 in systemic vitamin D regulation, and highlight independent local effects of intestinal CYP24A1, inhibition of which can alter mineral homeostasis without precipitating hypercalcemia. These findings indicate that tissue specific modulation of CYP24A1 activity could present a new theraputical pathway for the treatment of secondary hyperparathyroidism in CKD with a reduced risk of hypercalcemia compared to current treatments with vitamin D and its analogs.

Funding

• Other NIH Support