Extrarenal Expression of 25-Hydroxyvitamin D₃-1α-Hydroxylase¹

TLDR

1α‑hydroxylase catalyzes vitamin D activation in the kidney and is also expressed in multiple extrarenal tissues, but its function at these novel sites remains unclear. The study aims to map the extrarenal distribution of 1α‑hydroxylase in normal and diseased tissues using immunohistochemistry and Western blotting. Researchers employed specific RNA probes, antisera, immunohistochemical staining, and Western blot analysis to detect 1α‑hydroxylase mRNA and protein across mouse and human tissues. 1α‑hydroxylase was found in skin, lymph nodes, colon, pancreas, adrenal medulla, brain, and placenta, with overexpression in psoriatic skin and sarcoidosis, indicating a potential intracrine role in peripheral tissues.

Abstract

The mitochondrial enzyme 25-hydroxyvitamin D3-1α-hydroxylase (1α-hydroxylase) plays an important role in calcium homeostasis by catalyzing synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D3, in the kidney. However, enzyme activity assays indicate that 1α-hydroxylase is also expressed in a variety of extrarenal tissues; recent cloning of cDNAs for 1α-hydroxylase in different species suggests that a similar gene product is found at both renal and extrarenal sites. Using specific complementary ribonucleic acid probes and antisera to 1α-hydroxylase, we have previously reported the distribution of messenger ribonucleic acid and protein for the enzyme along the mouse and human nephron. Here we describe further immunohistochemical and Western blot analyses that detail for the first time the extrarenal distribution of 1α-hydroxylase in both normal and diseased tissues. Specific staining for 1α-hydroxylase was detected in skin (basal keratinocytes, hair follicles), lymph nodes (granulomata), colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex), and placenta (decidual and trophoblastic cells). Further studies using psoriatic skin highlighted overexpression of 1α-hydroxylase throughout the dysregulated stratum spinosum. Increased expression of skin 1α-hydroxylase was also associated with sarcoidosis. In lymph nodes and skin from these patients 1α-hydroxylase expression was observed in cells positive for the surface antigen CD68 (macrophages). The data presented here confirm the presence of protein for 1α-hydroxylase in several extrarenal tissues, such as skin, placenta, and lymph nodes. The function of this enzyme at novel extrarenal sites, such as adrenal medulla, brain, pancreas, and colon, remains to be determined. However, the discrete patterns of staining in these tissues emphasizes a possible role for 1α-hydroxylase as an intracrine modulator of vitamin D function in peripheral tissues.