Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice
Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf
Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf
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Research Article Metabolism Nephrology

Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice

Abstract

Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and is inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D, and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine, despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed, despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.

Authors

Michaela A.A. Fuchs, Alexander Grabner, Melody Shi, Susan L. Murray, Emily J. Burke, Nejla Latic, Venkataramana Thiriveedi, Jatin Roper, Shintaro Ide, Koki Abe, Hiroki Kitai, Tomokazu Souma, Myles Wolf

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Figure 7

Intestinal deletion of Cyp24a1 mitigates secondary hyperparathyroidism in a mouse model of kidney damage.

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Intestinal deletion of Cyp24a1 mitigates secondary hyperparathyroidism i...
(A) Kidney damage was induced in male VillinCreERT2Cyp24fl/fl mice and their Cre-negative littermates 1 week after the last tamoxifen injection by feeding them a 0.2% adenine containing diet supplemented with 1% calcium for 2 weeks (CKD diet). Additional VillinCreERT2Cyp24fl/fl and control mice were maintained on the same diet that lacked adenine (control diet). (B) Histological examination of kidney tissue indicated a similar level of kidney damage in VillinCreERT2Cyp24fl/fl mice and controls fed the CKD diet. (C) Measurement of glomerular filtration rate (GFR), BUN, and the qPCR markers of kidney fibrosis, Col1a1, and tubular injury, Kim1, confirmed kidney injury in all mice fed the CKD diet, but did not differ between VillinCreERT2Cyp24fl/fl mice and their controls on the CKD diet. (D) Compared with controls, VillinCreERT2Cyp24fl/fl mice demonstrate significantly lower PTH and FGF23 levels and unchanged serum calcium and phosphate after 2 weeks on the CKD diet. n ≥ 4 for all measurements. Results are mean ± SEM. Statistical significance was calculated by mixed effect analysis with Holm-Šidák’s correction. *P < 0.05; **P < 0.005; ****P < 0.0001. Representative images from ≥ 3 animals evaluated for each group. Scale bars: 100μm in B.