Vitamin D/VDR Protects Against Diabetic Kidney Disease by Restoring Podocytes Autophagy

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Abstract

Objective

The present study is to investigate the effect of vitamin D/Vitamin D Receptor (VDR) signaling on podocyte autophagy in diabetic nephropathy.

Methods

Kidney tissue sections from patients with diabetic nephropathy and nontumor kidney were checked under electronic microscope and VDR immunohistochemistry. Diabetic rat models were induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg). Calcitriol treatment was achieved by gavage at dose of 0.1μg/kg/d. Blood, urine and kidney tissue specimens were used for serum, urine biochemistry, histopathology and molecular biology testing. Podocyte cell line MPC-5 was cultured under hyperglycaemic conditions in the absence or presence of 100 nmol/L calcitriol to investigate podocyte injury and autophagy.

Results

VDR and autophagosomes in podocytes were significantly decreased in renal biopsy from patients with diabetic nephropathy, compared to healthy kidney tissue. Rats with STZ treatment developed typical diabetic kidney disease with low VDR expression. Calcitriol, the active form of vitamin D, could activate VDR and attenuate diabetic nephropathy including proteinuria and glomerular sclerosis. Calcitriol treatment also alleviated the podocyte foot process fusion, reduced podocyte injury marker desmin and preserved slit diaphragms proteins in diabetic nephropathy. Reduced LC3II/I, Beclin-1 and elevated p62 in renal homogenate and reduced autophagosomes and LC3II in podocytes indicated podocytes autophagy impairment in diabetic nephropathy. Whereas calcitriol treatment restored podocyte autophagy activities. In cultured podocytes, the protective effect of calcitriol against high glucose induced podocyte injury could be abated by autophagy inhibitor chloroquine.

Conclusion

Our study delivered the evidence that calcitriol/VDR signaling attenuated diabetic nephropathy and podocytes injury by restoring podocytes autophagy. This finding may have potential implication for exploring protective mechanisms of calcitriol/VDR in diabetic nephropathy.

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Most cited references 34

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Diabetic Kidney Disease: Challenges, Progress, and Possibilities.

Radica Z. Alicic, Michele Rooney, Katherine Tuttle (2017)

Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.

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Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

Mario Mauthe, Idil Orhon, Cecilia Rocchi … (2018)

Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradation. Autophagy is involved in the pathophysiology of numerous diseases and its modulation is beneficial for the outcome of numerous specific diseases. Several lysosomal inhibitors such as bafilomycin A1 (BafA1), protease inhibitors and chloroquine (CQ), have been used interchangeably to block autophagy in in vitro experiments assuming that they all primarily block lysosomal degradation. Among them, only CQ and its derivate hydroxychloroquine (HCQ) are FDA-approved drugs and are thus currently the principal compounds used in clinical trials aimed to treat tumors through autophagy inhibition. However, the precise mechanism of how CQ blocks autophagy remains to be firmly demonstrated. In this study, we focus on how CQ inhibits autophagy and directly compare its effects to those of BafA1. We show that CQ mainly inhibits autophagy by impairing autophagosome fusion with lysosomes rather than by affecting the acidity and/or degradative activity of this organelle. Furthermore, CQ induces an autophagy-independent severe disorganization of the Golgi and endo-lysosomal systems, which might contribute to the fusion impairment. Strikingly, HCQ-treated mice also show a Golgi disorganization in kidney and intestinal tissues. Altogether, our data reveal that CQ and HCQ are not bona fide surrogates for other types of late stage lysosomal inhibitors for in vivo experiments. Moreover, the multiple cellular alterations caused by CQ and HCQ call for caution when interpreting results obtained by blocking autophagy with this drug.

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Methods in mammalian autophagy research.

Noboru Mizushima, Tamotsu Yoshimori, Beth Levine (2010)

Autophagy has been implicated in many physiological and pathological processes. Accordingly, there is a growing scientific need to accurately identify, quantify, and manipulate the process of autophagy. However, as autophagy involves dynamic and complicated processes, it is often analyzed incorrectly. In this Primer, we discuss methods to monitor autophagy and to modulate autophagic activity, with a primary focus on mammalian macroautophagy. 2010 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Diabetes Metab Syndr Obes

Journal ID (iso-abbrev): Diabetes Metab Syndr Obes

Journal ID (publisher-id): dmso

Journal ID (pmc): dmso

Title: Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy

Publisher: Dove

ISSN (Electronic): 1178-7007

Publication date (Electronic): 16 April 2021

Publication date Collection: 2021

Volume: 14

Pages: 1681-1693

Affiliations

[1 ]Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang , Yichang, 443000, People’s Republic of China

[2 ]Three Gorges University College of Medical Science , Yichang, 443000, People’s Republic of China

[3 ]Department of Clinical Laboratory, The First Clinical Medical College of Three Gorges University, Center People’s Hospital of Yichang , Yichang, 443000, People’s Republic of China

[4 ]Center of Nephrology and Dialysis, Transplantation, Renmin Hospital of Wuhan University , Wuchang, Hubei, 430060, People’s Republic of China

Author notes

Correspondence: Jiefu Zhu; Shizhong Zhang Email sojeff@163.com; zhangsz@ctgu.edu.cn

[*]

These authors contributed equally to this work

Article

Publisher ID: 303018

DOI: 10.2147/DMSO.S303018

PMC ID: 8057803

PubMed ID: 33889003

SO-VID: 78838f09-5130-4385-8159-58172ba830f9

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 28 January 2021

Date accepted : 19 March 2021

Page count

Figures: 8, Tables: 6, References: 34, Pages: 13

Funding

Funded by: National Youth Science Foundation of China;

Funded by: Science and Technology Bureau Project of Yichang;

This work was supported by Grants from the National Youth Science Foundation of China (grant number 81600567), Science and Technology Bureau Project of Yichang (grant number A16-301-02). Zhixia Song and Chao Xiao are co-first authors in this publication.

Vitamin D/VDR Protects Against Diabetic Kidney Disease by Restoring Podocytes Autophagy

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Abstract

Objective

Methods

Results

Conclusion

Related collections

Journal of the ASEAN Federation of Endocrine Societies

Most cited references 34

Diabetic Kidney Disease: Challenges, Progress, and Possibilities.

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

Methods in mammalian autophagy research.

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