Vitamin D receptor activation protects against lipopolysaccharide-induced acute kidney injury through suppression of tubular cell apoptosis

Du, Jie; Jiang, Siqing; Hu, Zhaoxin; Tang, Shiqi; Sun, Yue; He, Ju-Liang; Li, Zhi; Yi, Bin; Wang, Jianwen; Zhang, Hao; Li, Yan Chun

doi:10.1152/ajprenal.00332.2018

Cited by 48 publications

(43 citation statements)

References 44 publications

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“…Azak A et al has reported that VDR activator paricalcitol could mitigate renal ischemia/reperfusion injury in rats 22 . Our quite recent work also showed a promising protection of vitamin D-VDR signaling against apoptosis in an AKI model induced by LPS 23 . In another way, supplementation of Vitamin D3 has also been reported to up-regulate VDR and decrease reduces cellular necrosis in lung tissue of mice infected by tuberculosis 24 .…”

Section: Discussionmentioning

confidence: 57%

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

et al. 2020

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Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

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Section: Discussionmentioning

confidence: 57%

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

et al. 2020

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“…Previous studies demonstrated that in different disease models, inhibition of apoptosis showed significant renal protective effects. Du et al [22] reported that the activation of vitamin D receptor protected against lipopolysaccharide-(LPS-) induced acute kidney injury by blocking renal tubular epithelial cell apoptosis. Huang et al [23] demonstrated that L3MBTL2, a novel polycomb group protein, improved renal injury by the p53 apoptosis pathway in renal tubular cells.…”

Section: Discussionmentioning

confidence: 99%

Shen Shuai II Recipe Attenuates Apoptosis in 5/6 Renal Ablation/Infarction Rats by Inhibiting p53 and the Mitochondrial Pathway of Apoptosis

Wang

Yang

Wang

2020

Oxidative Medicine and Cellular Longevity

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Background. Chronic kidney disease (CKD) is a global health burden with high mortality and morbidity. Clinical efficacy has been demonstrated for Shen Shuai II Recipe (SSR), an approved and widely used Chinese herbal medicine for over 20 years in China, to attenuate CKD progression. In this study, we explored the underlying molecular mechanisms of SSR benefits and studied its effects on apoptosis, a critical process in CKD development and progression. CKD was induced in rats with 5/6 renal ablation and infarction (A/I). Eight weeks after SSR treatment, we mainly assessed the severity of renal injury and fibrosis, the translocation of apoptotic factors in the mitochondrial apoptosis pathway, the degree of mitochondrial dysfunction, and the nuclear and mitochondrial translocation of p53. Furthermore, we detected the interaction of p53 with antiapoptotic Bcl-xL and Bcl-2 proteins. Our results showed that SSR significantly attenuated renal injury and fibrosis and inhibited the mitochondrial accumulation of proapoptotic proteins Bax and Puma and release of cytochrome c from mitochondria to the cytosol in a rat CKD model. In addition, SSR also improved the mitochondrial function and inhibited the nuclear and mitochondrial translocation of p53. In addition, SSR suppressed the p53 transactivation and the interaction of p53 with Bcl-xL and Bcl-2. These results suggested that SSR could block apoptosis in CKD by inhibiting p53 transcriptional-dependent and transcriptional-independent proapoptotic function and the mitochondrial pathway of apoptosis.

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“…Activation of VDR by paricalcitol protects against lipopolysaccharide (LPS)-induced acute kidney injury by blocking renal tubular epithelial cell apoptosis and preventing LPS-stimulated caspase 3 activation in the renal cortex of LPS-treated mice [57]. Paricalcitol administration also contributes to the modulation of renal inflammatory infiltration and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) expression by promoting VDR-mediated sequestration of NF-κB signaling [58].…”

Section: Vitamin D Protective Role In Tubular Damage In Ckdmentioning

confidence: 99%

Protective Role of Vitamin D in Renal Tubulopathies

et al. 2020

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Vitamin D is tightly linked with renal tubular homeostasis: the mitochondria of proximal convoluted tubule cells are the production site of 1α,25-dihydroxyvitamin D3. Patients with renal impairment or tubular injury often suffer from chronic inflammation. This alteration comes from oxidative stress, acidosis, decreased clearance of inflammatory cytokines and stimulation of inflammatory factors. The challenge is to find the right formula for each patient to correctly modulate the landscape of treatment and preserve the essential functions of the organism without perturbating its homeostasis. The complexity of the counter-regulation mechanisms and the different axis involved in the Vitamin D equilibrium pose a major issue on Vitamin D as a potential effective anti-inflammatory drug. The therapeutic use of this compound should be able to inhibit the development of inflammation without interfering with normal homeostasis. Megalin-Cubilin-Amnionless and the FGF23-Klotho axis represent two Vitamin D-linked mechanisms that could modulate and ameliorate the damage response at the renal tubular level, balancing Vitamin D therapy with an effect potent enough to contrast the inflammatory cascades, but which avoids potential severe side effects.

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Vitamin D receptor activation protects against lipopolysaccharide-induced acute kidney injury through suppression of tubular cell apoptosis

Cited by 48 publications

References 44 publications

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis

Shen Shuai II Recipe Attenuates Apoptosis in 5/6 Renal Ablation/Infarction Rats by Inhibiting p53 and the Mitochondrial Pathway of Apoptosis

Protective Role of Vitamin D in Renal Tubulopathies

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