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Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity

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Abstract

Purpose

Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency.

Methods

In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT.

Results

OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A.

Conclusion

Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.

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Data Availability

The data supporting the findings of this study are available on request.

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Acknowledgments

The authors would like to thank Ms. Naoko Horimoto for her technical assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (no.25870408) to KI, a grant from The Kidney Foundation, Japan (JKFB 13-36) to KI, and maxacalcitol (22-oxacalcitriol: OCT) was kindly provided by Chugai Pharmaceutical Co., Ltd.

Funding

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (no.25870408) to KI, a grant from The Kidney Foundation, Japan (JKFB 13–36) to KI and grants from Chugai Pharmaceutical Co., Ltd.

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Authors and Affiliations

  1. Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Kazunori Inoue, Isao Matsui, Ayumi Matsumoto, Karin Shimada, Seiichi Yasuda, Yusuke Katsuma, Yoshitsugu Takabatake & Yoshitaka Isaka

  2. Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Takayuki Hamano

  3. Department of Nephrology, Nagoya City University Graduate School of Medical Science and Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan

    Takayuki Hamano

  4. Cardiovascular Division, Osaka Saiseikai Senri Hospital, Suita, Osaka, 565-0862, Japan

    Keiji Okuda

  5. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yasumasa Tsukamoto & Yasushi Sakata

  6. Department of Nephrology, Tanaka Kitanoda Hospital, 707 Kitanoda, Sakai-ku, Sakai, Osaka, 599-8123, Japan

    Masaru Tanaka & Noriko Tanaka

  7. Department of Cardiology, Kansai Rosai Hospital, 3-1-69 Inabasou, Amagasaki, Hyogo, 660-8511, Japan

    Toshiaki Mano

  8. Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Graduate School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

    Tetsuo Minamino

Authors
  1. Kazunori Inoue
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  2. Isao Matsui
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  3. Takayuki Hamano
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  4. Keiji Okuda
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  15. Yasushi Sakata
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  16. Yoshitaka Isaka
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Kazunori Inoue, Isao Matsui, Keiji Okuda, Yasumasa Tsukamoto, Ayumi Matsumoto, Karin Shimada, Seiichi Yasuda, Yusuke Katsuma, Masaru Tanaka, Noriko Tanaka, and Takayuki Hamano. The first draft of the manuscript was written by Kazunori Inoue and Isao Matsui and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Isao Matsui.

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Conflict of Interest

The Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, received grants from Chugai Pharmaceutical Co., Ltd. The other authors have no conflicts of interest.

Ethics Approval

This retrospective cohort study was approved by the Ethics Committee (approval number: 2020-02) at Tanaka Kitanoda Hospital (Sakai-ku, Osaka, Japan).

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Patients who did not declare refusal to participation according to opt-out policy were enrolled in this retrospective study.

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Inoue, K., Matsui, I., Hamano, T. et al. Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity. Cardiovasc Drugs Ther 35, 381–397 (2021). https://doi.org/10.1007/s10557-020-07111-9

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