A review on the effects of vitamin D attenuating ischemia reperfusion injuries

Figures & data

Figure 1. Vitamin D3 structure and the pathway of its activation and inactivation in body. Vitamin D3 is synthesized from 7-dehydrocholesterol through UVB irradiation in skin. 25-hydroxylase enzyme converts vitamin D3 to 25-hydroxyvitamin D3 in liver. Then, 1α-hydroxylation produces the active vitamin D3(1,25-hydroxyvitamin D3). 25-hydroxyvitamin D3 and 1,25-hydroxyvitamin D3 can be further inactivated into 24,25-hydroxyvitamin D3 and 1,24,25-hydroxyvitamin D3.

Table 1. The protective effects of vitamin D and its analogs on renal I/R injury

Species	I/R Models	Treatments and doses	Effects and mechanisms	Ref
Sprague-Dawley rats	Both renal arteries I/R (45 min/24 h)	1,25 (OH)2 D3 (0.5 ug/kg, i.p) for 7 d before I/R	Inducing expressions of heat shock protein 70, ERK and proliferating cell nuclear antigen, inhibiting TNF-α mRNA and c-Jun N-terminal kinase expressions	^[Citation84]
C57BL/6 mice	Bilateral kidneys subjected to I/R (23 min/2 h)	Paricalcitol (0.3 μg/kg, i.p) at 24 h before I/R	Inhibiting renal inflammation via up-regulating COX-2 and PGE2	^[Citation85]
Wistar rats	Right nephrectomy, left renal I/R (45 min/45 min)	1,25 (OH)2 D3 (0.5 μg/kg,i.p) for 7 d before I/R	Ameliorating renal function injury (reduced alanine aminotransferase and aspartate aminotransferase) and apoptosis	^[Citation86]
Wistar rats	Right nephrectomy, left renal I/R (45 min/45 min)	1,25 (OH)2 D3(0.5 μg/kg,i.p) for 7 d before I/R	Ameliorating oxidative stress in kidneys	^[Citation87]
C57BL/6 mice	Bilateral renal I/R (28 min/24 h) by pedicle clamping	Paricalcitol (25 μg/kg, i.p) at 24 h before I/R	Decreasing infiltrations of neutrophil and macrophage, inflammatory reactions through suppressing TLR4/NF-κB	^[Citation88]
Wistar albino rats	Bilateral renal arteries I/R (45 min /24 h)	Paricalcitol (0.3 µg/kg in 0.1 mL,i.p) 24 hours before I/R	Decreasing the level and expression of matrix metalloproteinases	^[Citation89]
C57BL/6 J mice and HK-2 cells	Bilateral kidneys I/R (23 min/24 h); HK-2 cells I/R (90 min/15, 20 min)	Paricalcitol (0.3 μg/kg, i.p) at 24 h before I/R;2 ng/ml for 1 h in HK-2 cells	Decreasing oxidative stress, apoptosis, inflammations through increasing Akt, cyclic AMP responsive element binding protein (CREB) and suppressing NF-κB	^[Citation90]
Wister albino rats	I/R (30 min/96 h) by clamping both renal pedicles	22-oxacalcitriol (2-µg /kg,i.p.) 1 d before I/R	Decreasing renal cell apoptosis and fibrosis through repressing TLR, interferon gamma and NHE-1	^[Citation91]
Wister albino rats	Right nephrectomy, left renal I/R (45 min/24 h)	Pretreatment with paricalcitol for 7 days (0.2 μg/kg, i.p)	Improving tubular necrosis and medullar congestion	^[Citation92]
Wistar rats	Bilateral I/R (40 min/24 h)	Vitamin D (0.25,0.5, 1 μg/kg, i.p.) once daily for 7 d before I/R	Protecting I/R injury by activating PPAR-γ	^[Citation93]
Mice	Unilateral I/R by I/R(90 min/4,24 h)	Oral administration with cholecalciferol (25 μg/kg, at 48 h, 24 h, and 1 h) before I/R	Inhibiting renal NADPH oxidases, HO-1,and glutathione peroxidase	^[Citation94]
Sprague-Dawley rats	Bilateral renal I/R(45 min/24 h, 2 w)	Alfacalcidol (5 ng/kg/day, i.v.) 1 w before I/R; lasting until 2 w after I/R	Impeding inflammatory reaction and apoptosis, and activation of the renin-angiotensin system (RAS); activating Wnt4/β-catenin signal	^[Citation95]
Swiss Webster mice	Bilateral renal I/R(30 min /7 d)	Cholecalciferol (0,25 µg/kg, i.p) after renal ischemia	Reducing tubular, myofibroblast and macrophage numbers via repressing MCP-1 and TLR4 mRNA levels	^[Citation96]
Wistar rats	Right nephrectomy and left renal I/R(45 min/24 h)	Vitamin D3 (10 mg/ kg,i.p) before ischemia	Reducing impaired glomerular filtration rate and apoptosis via activating heat shock protein 70 and microRNA-21	^[Citation97]
Wistar rats	Both renal arteries I/R(45 min/90d)	Vitamin D3 (10,000 UI/kg diet)restored vitamin D deficiency to normal (<0.780 to 42.89 ng/mL)	Improving renal functions and hemodynamics, reducing the inflammation and fibrosis lesions	^[Citation98]

Table 2. The protective effects of vitamin D on cerebral I/R injury

Species	I/R Models	Treatments and dose	Effects and mechanisms		Ref
Mouse brain endothelial bEnd.3cells	Hypoxia/reperfusion (16 h/10 min)	1,25(OH)2D3 (100 nM) 24 h before H/R	Blocking decreases of tight junction proteins zonula occludin-1, claudin-5, and occludin, and increasing matrix metalloproteinase-9		^[Citation121]
Sprague-Dawley rats	Right middle cerebral artery I/R(90 min/4 d) with LPS-induced inflammation	Vitamin D (1 μg/kg, i.p.) at 5 min before reperfusion for 3 d	Restored peripheral immune dysfunctions		^[Citation122]
C57BL6 mice	Right middle cerebral artery I/R (1 h/24 h)	Vitamin D3 (100 ng/kg, i.p) for 5 d before I/R		Alleviating the development of cerebral infarction via reducing inflammations	^[Citation123]
C57Bl6 mice	Right middle cerebral artery I/R (1 h/23 h)	1,25 (OH)2D3 (100 ng/kg, i.p.) for 5 d before ischemia		Reducing infarct volume and exerting acute anti-inflammatory actions of vitamin D-replete mice	^[Citation124]
Sprague-Dawley rats	Global cerebral ischemia (10 min/30 min, 12 and 24 h)	Calcitriol at a dose of 1 μg/kg at 30 min, 12 and 24 h after I/R		Attenuating brain edema and neuronal apoptosis via ERK 1/2 activation	^[Citation125]
Sprague-Dawley rats	Middle cerebral artery (24 h/7d)	A single dose of 2 μg/kg after ischemia; or lasting 6 d		Protected the hippocampus from I/R injury from I/R injury through the NR3A/MEK/ERK/CREB	^[Citation126]
Wistar albino rats; primary cortical neurons	Right internal carotid arteryI/R(90 min/2 h); oxygen glucose deprivation/reoxygenation (2 h/24 h)	1,25 (OH)2D3 (1 μg/kg, i.p) for 8 d before I/R; 1, 20, 50, 75, 100, 500 nM and 1, 5 μM for 26 h		Improving cell death in vitro and functional effects in vivo	^[Citation127]
Sprague-Dawley rats	Common carotid arteries I/R (10 min/1, 2, and 3 d)	Paricalcitol (1 μg/kg, i.p) on days 1, 2, and 3 post-ischemia		Attenuating neuronal injury in the hippocampus	^[Citation128]
Sprague Dawley rats	Bilateral common carotid arteries I/R (10 min/ 3 d)	Calcitriol (1 μg/kg,i.p) at 30 min, 12 h, and 24 h after ischemia		Protecting against ischemia-induced cognitive impairments via apoptosis inhibited by activating VDR/ERK	^[Citation129]
Sprague Dawley rats	Left middle cerebral artery I/R (60 min/24 h)	Calcitriol (12 μg/kg, i.p, once) after ischemia		Attenuating brain injury, apoptosis and vasogenic edema by upregulating antioxidase activities and BDNF	^[Citation130]
Mongolian gerbils	Bilateral common carotid I/R (10 min/24 h)	Calcitriol (1 μg/kg/day, i.p. for 7 d) before I/R		Decreasing MMP9 and oxidative stress	^[Citation131]

Figure 2. The pathways of vitamin D attenuating I/R injuries. Vitamin Dattenuating I/R injuries by suppressing oxidative stress, inflammation, and apoptosis as well as improving proliferation and autophagy. Exogenous vitamin D alsorectified its deficiency and VDRs by improving LncRNA and Klotho levels, which also reduced vicious cycle between I/R injuries and the dysfunctions of vitamin D and VDRs.

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