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Inhibition of PDE7 Reduces Inflammatory Response Following Renal Ischemia/Reperfusion Injury
Author(s) -
Reis William R.,
Sun Michael A.,
Kronk Trinity A.,
Blount Mitsi A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.694.2
Subject(s) - medicine , kidney , chemokine , blood urea nitrogen , ischemia , reperfusion injury , acute kidney injury , transplantation , cytokine , endocrinology , inflammation , renal function , immune system , immunology
Ischemia/reperfusion (I/R) injury is an unavoidable consequence after kidney transplantation. I/R affects many regulatory systems to promote pro‐inflammatory responses leading to the progressive interstitial renal fibrosis and declining renal function that can negatively impact long‐term graft outcome. Because elevated cAMP can offset the this harmful, sustained immune response, identification of a targetable protein to increase kidney cAMP levels may provide a viable option to prevent I/R injury before organ recovery by donor pretreatment. Our studies aimed to determine the benefits of raising renal cAMP levels through phosphodiesterase‐7 (PDE7) inhibition for treating the immune response following I/R insult. PDE7 inhibition following TNF‐alpha stimulation of human proximal cells (HK‐2) reduced mRNA expression of cytokines (IL‐2, IL‐6, IL‐12β, IL‐18) and chemokines (CCL2, CCL5) to sham‐treatment levels. Next, age‐matched, male Sprague‐Dawley rats were treated with vehicle or PDE7 inhibitor (TC3.6) 24‐hours before ischemia‐reperfusion (I/R) was induced by inhibiting bilateral renal circulation of for 30 minutes. Perfusion was restored and rats recovered in metabolic cages for 24 hours before sacrificed to collect blood, urine and kidney tissue. Sham surgery was also performed on untreated and TC3.6‐treated rats. I/R injury increased mRNA expression of pro‐inflammatory cytokines and chemokines in whole kidney tissue from vehicle‐treated rats. However, when the rats were treated with TC3.6 prior to I/R injury, cytokine and chemokine mRNA expression was reduced to levels comparable to sham surgery rats. Blood urea nitrogen (BUN) was elevated in vehicle‐treated rats following I/R injury compared to vehicle‐ and TC3.6‐treated rats following sham surgery; however, BUN was reduced in I/R injured TC3.6‐treated rats. In conclusion, PDE7 inhibition prior to I/R injury attenuates pro‐inflammatory responses in the kidney and protects renal function following insult. Our findings provide evidence that PDE7 inhibition may be an effective pretreatment prior to kidney transplant to reduce the harmful effects of I/R and improve graft outcome.