Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet

Abstract

Vascular calcification is common in chronic kidney disease, where cardiovascular mortality remains the leading cause of death. Patients with kidney disease are often prescribed vitamin D receptor agonists (VDRAs) that confer a survival benefit, but the underlying mechanisms remain unclear. Here we tested two VDRAs in a mouse chronic kidney disease model where dietary phosphate loading induced aortic medial calcification. Mice were given intraperitoneal calcitriol or paricalcitol three times per week for three weeks. These treatments were associated with half of the aortic calcification compared to no therapy, and there was no difference between the two agents. In the setting of a high phosphate diet, serum parathyroid hormone and calcium levels were not significantly altered by treatment. VDRA therapy was associated with increased serum and urine klotho levels, increased phosphaturia, correction of hyperphosphatemia, and lowering of serum fibroblast growth factor-23. There was no effect on elastin remodeling or inflammation, however, the expression of the anti-calcification factor, osteopontin, in aortic medial cells was increased. Paricalcitol upregulated osteopontin secretion from mouse vascular smooth muscle cells in culture. Thus, klotho and osteopontin were upregulated by VDRA therapy in chronic kidney disease, independent of changes in serum parathyroid hormone and calcium.

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

“…Indeed, α‐Klotho deficiency in mice leads to a limited vasodilatory response and increased permeability in the endothelial cells among other vascular complications also observed in CKD patients 22, 23, 24, 41. As reported previously in other uremic in vivo models20, 21 and CKD patients,42, 43 we confirmed that impaired kidney function induced downregulation of mRNA and α‐Klotho protein levels in kidney tissue accompanied by lower serum concentrations. However, it was unexpected that neither vitamin D deficiency nor paricalcitol supplementation affected α‐Klotho in the kidney tissue or its concentration in serum.…”

“…Only in paricalcitol‐treated, vitamin D–sufficient animals, a nonsignificant trend was noted. Consistent with this suggestion of increase, Lau et al found, in intraperitoneally paricalcitol (100 and 300 ng/kg) treated uremic mice on a high‐phosphate diet, increased serum α‐Klotho concentrations despite unchanged kidney tissue expression, leaving the origin of the increment elusive 20. In this experiment, we applied similar paricalcitol concentrations (100 ng/kg) as in that study and mimicked the clinical setting by applying an oral, instead of intraperitoneal, route of administration, which might have limited the efficacy on serum α‐Klotho concentrations in our animal model.…”

“…Instead of a direct effect on target tissue, as an alternative explanation for beneficial effects of active vitamin D, it has been postulated that it can upregulate renal α‐Klotho as the actual effector of remote beneficial effects, after shedding its ectodomain 20, 21, 39, 40. Indeed, α‐Klotho deficiency in mice leads to a limited vasodilatory response and increased permeability in the endothelial cells among other vascular complications also observed in CKD patients 22, 23, 24, 41.…”

“…A small number of prior studies have suggested benefits of the active vitamin D analogue paricalcitol on endothelial stability in animal models of CKD16, 17 and even in patients 18, 19. Interestingly, paricalcitol supplementation increased kidney and serum α‐Klotho levels in in vivo models of CKD 20, 21. α‐Klotho is an antiaging protein, and its deficiency is associated with a cardiovascular phenotype including arteriosclerosis, vascular calcification, and, importantly, endothelial cell dysfunction 22, 23.…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…Vitamin D receptor agonists may effectively inhibit both the TGF-␣-converting enzyme/TGF␣/EGF receptor pathway and the RAAS in the parathyroid and kidney 90,91 and reduce vascular calcification, podocyte damage, 63,[92][93][94] and proteinuria through blockade of Wnt/␤-catenin signaling. 95 Vitamin D receptor agonists also may upregulate klotho 96 and exert an antiinflammatory action through the reduction of nuclear factor B. These actions may explain in part the nephroprotective effects and reduced mortality observed in patients treated with vitamin D receptor agonists independent of serum 25-dehydroxyvitamin D levels.…”