15-Hydroxyprostaglandin dehydrogenase inhibitor prevents contrast-induced acute kidney injury

Abstract

The two primary mechanisms by which iodinated contrast media (CM) causes contrast-induced acute kidney injury (CIAKI) are the hemodynamic effect causing intrarenal vasoconstriction and the tubular toxic effect causing acute tubular necrosis. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), which degrades prostaglandin E 2 (PGE2), promotes tissue repair and regeneration in many organs. PGE2 causes intrarenal arterial vasodilation. In this study, we investigated whether a 15-PGDH inhibitor can act as a candidate for blocking these two major mechanisms of CIAKI. We established a CIAKI mouse model by injecting a 10 gram of iodine per body weight (gI/kg) dose of iodixanol into each mouse tail vein. A 15-PGDH inhibitor (SW033291), PGE1, or PGE2 were administered to compare the renal functional parameters, histologic injury, vasoconstriction, and renal blood flow changes. In addition, human renal proximal tubular epithelial cells were cultured in a CM-treated medium. SW033291, PGE1, or PGE2 were added to compare any changes in cell viability and apoptosis rate. CIAKI mice that received SW033291 had lower serum levels of creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1 ( p < 0.001); lower histologic injury score and TUNEL positive rates ( p < 0.001); and higher medullary arteriolar area ( p < 0.05) and renal blood flow ( p < 0.001) than CM + vehicle group. In cell culture experiments, Adding SW033291 increased the viability rate ( p < 0.05) and decreased the apoptosis rate of the tubular epithelial cells ( p < 0.001). This 15-PGDH inhibitor blocks the two primary mechanisms of CIAKI, intrarenal vasoconstriction and tubular cell toxicity, and thus has the potential to be a novel prophylaxis for CIAKI. Abbreviations: 15-PGDH: 15-hydroxyprostaglandin dehydrogenase; AMP: adenosine monophosphate; CIAKI: contrast-induced acute kidney injury; CM: contrast media; EP: prostaglandin E2 receptor; hRPTECs: human-derived renal proximal tubule epithelial cells; KIM-1: kidney injury molecule-1; MTT: 3-(4,5-Dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NGAL: neutrophil gelatinase-associated lipocalin; PBS: phosphate-buffered saline; PGE1: prostaglandin E 1 ; PGE2: prostaglandin E 2 ; RBF: renal blood flow; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; α-SMA: α-Smooth muscle actin

Role of prostaglandin E2 in tissue repair and regeneration

“…Interestingly, a combination treatment of PGE2 and SW033291 increases the success rate of PGE2 alone-induced cervical ripening in mice 167 , which should be considered in labor resulting from an unfavorable perinatal environment. Besides, since PGE2 induces vasodilation of intrarenal arteries and alleviates acute kidney injury to a certain degree, researchers also, respectively, applied SW033291 to treat contrast-induced 168 and LPS-induced 169 acute kidney injury in addition to I/R induced kidney injury 22 . Consequently, SW033291 blocks intrarenal vasoconstriction as well as renal tubular cytotoxicity in contrast-induced acute kidney ischemia injury 168 , while increasing the survival rate and ameliorating injury via preventing apoptosis, oxidative stress, and facilitating autophagy in LPS-induced kidney injury models 169 .…”

“…Besides, since PGE2 induces vasodilation of intrarenal arteries and alleviates acute kidney injury to a certain degree, researchers also, respectively, applied SW033291 to treat contrast-induced 168 and LPS-induced 169 acute kidney injury in addition to I/R induced kidney injury 22 . Consequently, SW033291 blocks intrarenal vasoconstriction as well as renal tubular cytotoxicity in contrast-induced acute kidney ischemia injury 168 , while increasing the survival rate and ameliorating injury via preventing apoptosis, oxidative stress, and facilitating autophagy in LPS-induced kidney injury models 169 . Additionally, a large number of reports show the protective effects of PGE2 in the bleomycin model.…”

A novel contrast-induced acute kidney injury mouse model based on low-osmolar contrast medium

“…Fortunately, a novel CI-AKI model was successfully built with C57BL/6 mouse as the background in our current study. Exposing healthy animal to contrast medium alone can rarely induce acute kidney injury [ 37 ] and by searching PubMed online articles, only one article about establishing a female mouse model of CIN by 10 gram of iodine per body weight (gI/kg) dose of iodixanol was found [ 23 ]. Thus, considering the sex difference [ 22 , 25 ], the pretreatments especially being more similar to the risk factors for human kidney damage compared to the interference of medicine such as indomethacin is still crucial to build a CI-AKI male mouse model.…”

“…When it comes to the reasons for the dose and type selection of iodinated contrast media and four weeks after the UPHT surgery as being the time selection, firstly, LOCM (iohexol, 10 mL/kg) is widely used in the previous study [ 21 , 23 ]. Although one study successfully adopted 15 mL/kg iohexol combined with dehydration plus furosemide (10 mL/kg) to establish CIN rat model [ 19 ], based on the principle of emphasizing the importance of minimizing the dose of CM in clinical practice, LOCM (iohexol, 10 mL/kg) combined with the proper pretreatment is enough to construct male mice model with CI-AKI.…”

“…The study was divided into three phases ( Figure 1 ). The first phase includes multiple water deprivation pretreatment plans to find whether only water deprivation without furosemide combined with LOCM (iohexol, 10 mL/kg as previously described by other studies [ 21 , 23 ]) and UPHT can induce AKI in mice ( Figure 1(A) ). The length of water deprivation was according to previous documents [ 19 ].…”