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25 May 2020 : Animal Research  

Roflumilast, a Phosphodiesterases-4 (PDE4) Inhibitor, Alleviates Sepsis‑induced Acute Kidney Injury

Xingkai Xu1BCDEF, Lulei Liao1BCDE, Baisheng Hu1BCD, Hao Jiang1ABCDEF*, Meichun Tan1ABCDEF

DOI: 10.12659/MSM.921319

Med Sci Monit 2020; 26:e921319


BACKGROUND: Sepsis causes acute kidney injury (AKI) in critically ill patients. Roflumilast, a phosphodiesterases-4 (PDE4) inhibitor, has been shown to be therapeutically effective in sepsis-induced organ injury. However, the function of roflumilast in sepsis-induced AKI is not clearly understood. The present study aimed to explore the protective effect of roflumilast on sepsis-induced AKI in mice.

MATERIAL AND METHODS: A sepsis model was established by cecal ligation and puncture surgery. Roflumilast (1 mg/kg and 3 mg/kg) was used once daily for 7 consecutive days for treatment. Kidney tissues were pathologically examined by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The levels of kidney injury markers including blood urea nitrogen (BUN), creatinine (Cre), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β were detected by their corresponding test kits. The protein expression was measured using western blot and cell apoptosis of kidney tissue was determined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay.

RESULTS: Roflumilast was demonstrated to alleviate sepsis-induced AKI by reducing histopathological changes and decreasing the levels of kidney injury markers in a concentration-dependent way. The production of TNF-α, IL-6, and IL-1β was significantly suppressed by roflumilast. Besides, roflumilast inhibited the activation of NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells). Additionally, roflumilast inhibited cell apoptosis and changes in expression of apoptosis related proteins induced by sepsis. Finally, high concentration of roflumilast (3 mg/kg) did not have an adverse effect on liver, heart, lung, or spleen.

CONCLUSIONS: Our study indicated that roflumilast could ameliorate AKI induced by sepsis through restraining inflammatory response and apoptosis of the kidney, providing a molecular basis for a novel medical treatment of septic AKI.

Keywords: Acute Kidney Injury, Apoptosis, Inflammation, Phosphodiesterase 4 Inhibitors, Sepsis, Aminopyridines, Benzamides, Blood Urea Nitrogen, Creatinine, Cyclic Nucleotide Phosphodiesterases, Type 4, Cyclopropanes, Cytokines, Hepatitis A Virus Cellular Receptor 1, Kidney, Lipocalin-2, Mice, Inbred BALB C, NF-kappa B



01 December 2021 : Editorial  

Editorial: Cardiovascular Complications at One Year After SARS-CoV-2 Infection are Independent of Underlying Cardiovascular Risk Factors or Severity of COVID-19

Dinah V. Parums
Science Editor, Medical Science Monitor, International Scientific Information, Inc., Melville, NY, USA

DOI: 10.12659/MSM.937048

Med Sci Monit 2022; 28:e937048


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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750