Excess 25-hydroxyvitamin D3 exacerbates tubulointerstitial injury in mice by modulating macrophage phenotype

Kusunoki, Yasuo; Matsui, Isao; Hamano, Takayuki; Shimomura, Atsushi; Mori, Daisuke; Yonemoto, Sayoko; Takabatake, Yoshitsugu; Tsubakihara, Yoshiharu; St‐Arnaud, René; Isaka, Yoshitaka; Rakugi, Hiromi

doi:10.1038/ki.2015.210

Cited by 27 publications

(21 citation statements)

References 61 publications

(79 reference statements)

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“…No data from these studies have suggested that ER calcifediol has an adverse effect on renal function; mean serum Cr increase and mean eGFR decline were similar in the active and placebo groups. High serum concentrations of 25-hydroxyvitamin D 3 (>300 ng/ml) have been reported to exacerbate tubular interstitial injury in CYP27B1 knockout mice [23] , but these levels were much greater than those recorded in the present studies. Mean adherence to study drug was over 95% in all studies.…”

Section: Discussioncontrasting

confidence: 86%

Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

Sprague

Crawford²,

Melnick

et al. 2016

Am J Nephrol

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Background/Aims: Vitamin D insufficiency and secondary hyperparathyroidism (SHPT) are associated with increased morbidity and mortality in chronic kidney disease (CKD) and are poorly addressed by current treatments. The present clinical studies evaluated extended-release (ER) calcifediol, a novel vitamin D prohormone repletion therapy designed to gradually correct low serum total 25-hydroxyvitamin D, improve SHPT control and minimize the induction of CYP24A1 and FGF23. Methods: Two identical multicenter, randomized, double-blind, placebo-controlled studies enrolled subjects from 89 US sites. A total of 429 subjects, balanced between studies, with stage 3 or 4 CKD, SHPT and vitamin D insufficiency were randomized 2:1 to receive oral ER calcifediol (30 or 60 µg) or placebo once daily at bedtime for 26 weeks. Most subjects (354 or 83%) completed dosing, and 298 (69%) entered a subsequent open-label extension study wherein ER calcifediol was administered without interruption for another 26 weeks. Results: ER calcifediol normalized serum total 25-hydroxyvitamin D concentrations (>30 ng/ml) in >95% of per-protocol subjects and reduced plasma intact parathyroid hormone (iPTH) by at least 10% in 72%. The proportion of subjects receiving ER calcifediol who achieved iPTH reductions of ≥30% increased progressively with treatment duration, reaching 22, 40 and 50% at 12, 26 and 52 weeks, respectively. iPTH lowering with ER calcifediol was independent of CKD stage and significantly greater than with placebo. ER calcifediol had inconsequential impact on serum calcium, phosphorus, FGF23 and adverse events. Conclusion: Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.

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Section: Discussioncontrasting

confidence: 86%

Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

Sprague

Crawford²,

Melnick

et al. 2016

Am J Nephrol

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“…In this study, serum 1,25D levels increased as well as 25D levels, suggesting that the benefit of vitamin D replacement stems from an increase in 1,25D. Notably, we reported recently that administration of massive amounts of 25D exacerbates renal fibrosis in the UUO kidney in 1alpha-hydroxylase knockout mice, which cannot convert 25D to 1,25D [ 49 ]. Therefore, 25D, per se, is unlikely to protect the kidney without conversion to 1,25D.…”

Section: Which Is Renoprotective Native D or Active D?mentioning

confidence: 52%

Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015

Hamano

2017

Clin Exp Nephrol

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Bone fracture, cardiovascular events, and mortality are three outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD), and the umbrella concept originally described for dialysis patients. The reported association of serum phosphorus or fibroblast growth factor 23 (FGF23) levels with renal outcome suggests that the fourth relevant outcome of CKD-MBD in predialysis patients is renal outcome. We found that proteinuria of 2+ or greater with a dipstick test was associated with low vitamin D status due to urinary loss of 25-hydroxyvitamin D (25D). Moreover, active vitamin D or its analogues decrease proteinuria. Given our finding that maxacalcitol does not repress renin, the reduction of proteinuria by this agent is likely due to direct upregulation of the nephrin and podocin in podocytes. Moreover, this agent downregulates the mesenchymal marker desmin in podocytes and blocks transforming growth factor—beta autoinduction, leading to attenuation of renal fibrosis in a unilateral ureteral obstructive (UUO) model. These facts are reminiscent of the suppression of epithelial–mesenchymal transition (EMT) by vitamin D. EMT blockage may explain our finding that vitamin D prescription in renal transplant recipients is associated with a lower incidence of cancer. We also reported that low vitamin D status and high FGF23 levels predict a worse renal outcome. However, administration of massive doses of 25D exacerbates renal fibrosis in UUO kidneys in 1alpha-hydroxylase knockout mice. Moreover, FGF23 inhibits 1alpha-hydroxylase in proximal tubules and monocytes. Taken together, local 1,25(OH)2D in the kidney tissue but not 25D seems to protect the kidney.

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“…Quantitative RT-PCRQuantitative RT-PCR was performed as described previously(27). Primers were as follows: nucleotide binding domain, leucine-rich repeats-containing family,pyrin domain-containing (NLRP) 3, 59-ATGCTGCTTCGACATCTC CT-39 and 59-AACCAATGCGAGATCCTGAC-39; apoptotic speck protein containing a caspase recruitment domain (ASC), 59-ACAGAAGTGGACGGAGTGCT-39 and 59-CTCCA GGTCCATCACCAAGT-39; caspase-1, 59-CACAGCTCTGGA GATGGTGA-39 and 59-TCTTTCAAGCTTGGGCACTT-39; MCP-1, 59-CCCAATCAGTAGGCTGGAGA-39 and 59-TCTG GACCCATTCCTTCTTG-39; NGAL, 59-CTACAACCAGTTCG CCATGG-39 and 59-ACACTCACCACCCATTCAGT-39; a-SMA, 59-AGATCAAGATCATTGCCCCTCC-39 and 59-TTGTGTGCTA GAGGCAGAGC-39; collagen type I, 59-ACGCCATCAAGGTCT ACTGC-39 and 59-ACTCGAACGGGAATCCATCG-39; and 18S ribosomal RNA, 59-AAACGGCTACCACATCCAAG-39 and 59-CCTCCAATGGATCCTCGTTA-39.…”

mentioning

confidence: 99%

Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules

et al. 2017

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Advanced glycation end products (AGEs) are involved in the progression of diabetic nephropathy. AGEs filtered by glomeruli or delivered from the circulation are endocytosed and degraded in the lysosomes of kidney proximal tubular epithelial cells (PTECs). Autophagy is a highly conserved degradation system that regulates intracellular homeostasis by engulfing cytoplasmic components. We have recently demonstrated that autophagic degradation of damaged lysosomes is indispensable for cellular homeostasis in some settings. In this study, we tested the hypothesis that autophagy could contribute to the degradation of AGEs in the diabetic kidney by modulating lysosomal biogenesis. Both a high-glucose and exogenous AGE overload gradually blunted autophagic flux in the cultured PTECs. AGE overload upregulated lysosomal biogenesis and function in vitro, which was inhibited in autophagy-deficient PTECs because of the impaired nuclear translocation of transcription factor EB. Consistently, streptozotocin-treated, PTEC-specific, autophagy-deficient mice failed to upregulate lysosomal biogenesis and exhibited the accumulation of AGEs in the glomeruli and renal vasculature as well as in the PTECs, along with worsened inflammation and fibrosis. These results indicate that autophagy contributes to the degradation of AGEs by the upregulation of lysosomal biogenesis and function in diabetic nephropathy. Strategies aimed at promoting lysosomal function hold promise for treating diabetic nephropathy.

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Excess 25-hydroxyvitamin D3 exacerbates tubulointerstitial injury in mice by modulating macrophage phenotype

Cited by 27 publications

References 61 publications

Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease

Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015

Autophagy Inhibits the Accumulation of Advanced Glycation End Products by Promoting Lysosomal Biogenesis and Function in the Kidney Proximal Tubules

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