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

Abstract

The mitochondrial enzyme 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-hydroxylase) plays an important role in calcium homeostasis by catalyzing synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D(3), in the kidney. However, enzyme activity assays indicate that 1 alpha-hydroxylase is also expressed in a variety of extrarenal tissues; recent cloning of cDNAs for 1 alpha-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 1 alpha-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 1 alpha-hydroxylase in both normal and diseased tissues. Specific staining for 1 alpha-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 1 alpha-hydroxylase throughout the dysregulated stratum spinosum. Increased expression of skin 1alpha-hydroxylase was also associated with sarcoidosis. In lymph nodes and skin from these patients 1 alpha-hydroxylase expression was observed in cells positive for the surface antigen CD68 (macrophages). The data presented here confirm the presence of protein for 1 alpha-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 1 alpha-hydroxylase as an intracrine modulator of vitamin D function in peripheral tissues.

CYP27B1 null mice with LacZ reporter gene display no 25-hydroxyvitamin D 3 -1α-hydroxylase promoter activity in the skin

“…The 1␣-hydroxylase promoter activity we report stands in stark contrast to that reported by Hewison and coworkers (28). In their study, 1␣-hydroxylase expression was probed in histologically normal human tissue sections with a polyclonal antiserum, and positive staining was reported in the skin, lymph nodes, colon, pancreas, adrenal medulla, brain, and placenta.…”

“…This observation is consistent with previous studies of isolated nephrons from vitamin D-deficient rats, chickens, and rabbits, all of which reported localization of 1␣-hydroxylase activity to the proximal tubules (52)(53)(54)(55). Given the extensive staining of the distal nephrons reported by Hewison and coworkers (28), our reporter assay system should have easily detected 1␣-hydroxylase promoter activity in the renal medulla. No such activity was ever observed in either the vitamin Ddeficient or -sufficient state.…”

“…Bikle et al (26) have also reported 1,25(OH) 2 D 3 production in perfused flaps of porcine skin. Local production of 1,25(OH) 2 D 3 has been proposed to regulate cellular function and͞or differentiation in an autocrine or paracrine fashion (18,19,24,27,28), and it has been suggested that keratinocytes could supply 1,25(OH) 2 D 3 to the systemic circulation when renal production of the hormone is impaired (26,29). Production of extrarenal 1,25(OH) 2 D 3 in these experiments is not supported, however, by in vivo metabolic studies in nephrectomized nonpregnant rats.…”

Mineral metabolism disturbances in patients with chronic kidney disease

“…These intriguing data corroborate experimental findings that indicate protection of podocyte injury and glomerulosclerosis with vitamin D therapy [105,[109][110][111]. Another emerging treatment strategy for vitamin D deficiency in CKD is supplementation with high doses of non-activated vitamin D, which may be activated by non-renal 1-alpha hydroxylase in early CKD [112,113]. This exciting treatment strategy is motivated by low cost, physiological vitamin D replacement, and few side-effects; however, as yet there is little published evidence to support its use.…”

Hypovitaminosis D in pregnancy and its correlation with preeclampsia and gestational diabetes mellitus

“…Vitamin D receptors 7 and 1αhydroxylase are expressed both in decidua and trophoblast cells, providing an evidence for role of vitamin D in placentation. 8 Gestational diabetes mellitus (GDM) and impaired glucose tolerance (IGT) affect maternal, foetal and neonatal well-being. The prevalence of GDM is increasing globally.…”