vitamin-d-2 and Reperfusion-Injury

The protective mechanism of paricalcitol remains unclear in renal ischemia-reperfusion (IR) injury. We investigated the renoprotective effects of paricalcitol in IR injury through the prostaglandin E

Topics: Animals; Apoptosis; Ergocalciferols; Kidney; Kidney Diseases; Male; Mice; Oxidative Stress; Proto-Oncogene Proteins c-akt; Receptors, Prostaglandin E, EP4 Subtype; Reperfusion Injury; Second Messenger Systems; Transcription Factor RelA

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). The inflammatory response that drives IRI involves upregulation of matrix metalloproteinases (MMPs), which results in proteolytic degradation of renal microvascular matrix. Evidence suggests a potential protective role of active vitamin D on ischemic injury by downregulating MMPs. In the present study, we aimed to determine the expression and level of MMP-2 and MMP-9 in renal IRI model and the potential beneficial effect of paricalcitol on both level and expression of MMPs and tubular injury caused by IRI.. 20 Wistar albino rats were divided into three groups: sham-operated, ischemia-reperfusion, and paricalcitol-pretreated. IRI model was induced by bilateral clamping of renal arteries for 45 minutes followed by 24 hours of reperfusion. The analysis of serum creatinine and levels of MMPs were performed after 24 hours of IRI. The effects of paricalcitol on the quantity and expression of MMP-2 and MMP-9 in renal tubular epithelial cells were investigated by enzyme-linked immunosorbent assay and immunohistochemistry, respectively. The pathological examinations were performed to score tubular damage by light microscopy.. Creatinine levels decreased in the paricalcitol group, although this was not proven to be significant. Rats in the paricalcitol group showed significant decrease in both level and expression of MMPs and in tubular injury scores as compared to the IRI group.. Paricalcitol may attenuate renal tubular injury caused by IRI by decreasing both level and expression of MMPs. Further studies are required to investigate the interplay between activated vitamin D and MMPs in AKI.
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Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Ergocalciferols; Kidney; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Wistar; Reperfusion Injury

The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between vascular endothelial cell dysfunction, inflammation, and tubular cell damage. Several lines of evidence suggest a potential anti-inflammatory effect of vitamin D in various kidney injury models. In this study, we investigated the effect of paricalcitol, a synthetic vitamin D analog, on renal inflammation in a mouse model of ischemia/reperfusion (I/R) induced acute kidney injury (AKI).. Paricalcitol was administered via intraperitoneal (IP) injection at 24h before ischemia, and then I/R was performed through bilateral clamping of the renal pedicles. Twenty-four hours after I/R, mice were sacrificed for the evaluation of injury and inflammation. Additionally, an in vitro experiment using HK-2 cells was also performed to examine the direct effect of paricalcitol on tubular cells.. Pre-treatment with paricalcitol attenuated functional deterioration and histological damage in I/R induced AKI, and significantly decreased tissue neutrophil and macrophage infiltration and the levels of chemokines, the pro-inflammatory cytokine interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). It also decreased IR-induced upregulation of Toll-like receptor 4 (TLR4), and nuclear translocation of p65 subunit of NF-κB. Results from the in vitro study showed pre-treatment with paricalcitol suppressed the TNF-α-induced depletion of cytosolic IκB in HK-2 cells.. These results demonstrate that pre-treatment with paricalcitol has a renoprotective effect in ischemic AKI, possibly by suppressing TLR4-NF-κB mediated inflammation.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Cell Line; Chemokine CCL2; Chemokines; Creatine; Ergocalciferols; Humans; I-kappa B Kinase; Inflammation; Interleukin-6; Kidney; Macrophages; Male; Mice; Mice, Inbred C57BL; Neutrophils; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA

Despite the developments in modern medicine, acute renal injury is still a challenging and common health problem. It is well known that ischaemia and reperfusion takes place in pathological mechanisms. Efforts to clarify the pathophysiology and interventions to improve outcomes are essential. Our study aimed to investigate whether the prophylactic use of paricalcitol is beneficial in renal ischaemia/reperfusion (I/R) injury.. Twenty-four Wistar albino rats were assigned randomly to four groups. Right nephrectomies were performed at the time of renal arterial clamping. Sham surgery was performed on the rats in group 1. For the rats in group 2, the left renal artery was clamped for 45 minutes. The rats in group 3 received paricalcitol for seven days (0.2μg/kg/day); following this, a right nephrectomy and left renal arterial clamping were not performed. The rats in group 4 received paricalcitol for seven days (0.2μg/kg/day); following this, a right nephrectomy and left renal arterial clamping for 45 minutes were performed. Tissue thiobarbituric acid reactive substances (TBARS), superoxide dismutase, sulfhydryl groups as well as nitric oxide metabolites, serum urea and creatinine levels were measured for all four groups.. In group 4, there were some improvements in terms of TBARS, nitrite, nitrate, superoxide dismutase and creatinine levels. In the histopathological evaluation, paricalcitol therapy improved tubular necrosis and medullar congestion but there was no significant difference in terms of tubular cell swelling, cellular vacuolisation or general damage. Immunohistopathological examination revealed lower scores for vascular endothelial growth factor in the group 4 rats than in group 2.. Paricalcitol therapy improved renal I/R injury in terms of serum and histopathological parameters. These potential beneficial effects need to be further investigated.

Topics: Acute Kidney Injury; Animals; Constriction; Ergocalciferols; Immunohistochemistry; Kidney; Nephrectomy; Nitric Oxide; Oxidoreductases; Random Allocation; Rats; Rats, Wistar; Receptors, Calcitriol; Reperfusion Injury; Thiobarbituric Acid Reactive Substances

The effect of paricalcitol on renal ischemia-reperfusion injury (IRI) has not been investigated. We examined whether paricalcitol is effective in preventing inflammation in a mouse model of IRI, and evaluated the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways as a protective mechanism of paricalcitol.. Paricalcitol (0.3 μg/kg) was administered to male C57BL/6 mice 24 h before IRI. Bilateral kidneys were subjected to 23 min of ischemia, and mice were killed 72 h after IRI. The effects of paricalcitol on renal IRI were evaluated in terms of renal function, tubular necrosis, apoptotic cell death, inflammatory cell infiltration and inflammatory cytokines. The effects of paricalcitol on COX-2, PGE2 and its receptors were investigated.. Paricalcitol pretreatment improved renal function (decreased blood urea nitrogen and serum creatinine levels), tubular necrosis and apoptotic cell death in IRI-mice kidneys. The infiltration of inflammatory cells (T cells and macrophages), and the production of proinflammatory cytokines (RANTES, tumor necrosis factor-α, interleukin-1β and interferon-γ) were reduced in paricalcitol-treated mice with IRI. Paricalcitol up-regulated COX-2 expression, PGE2 synthesis and mRNA expression of receptor subtype EP4 in post-ischemic renal tissue. The cotreatment of a selective COX-2 inhibitor with paricalcitol restored functional injury and tubular necrosis in paricalcitol-treated mice with IRI.. Our study demonstrates that paricalcitol pretreatment prevents renal IRI via the inhibition of renal inflammation, and the up-regulation of COX-2 and PGE2 is one of the protective mechanisms of paricalcitol in renal IRI.

Topics: Animals; Blotting, Western; Bone Density Conservation Agents; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Ergocalciferols; Immunoenzyme Techniques; Inflammation; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Receptors, Calcitriol; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger