Title: Early antihypertensive treatment and ischemia-induced acute kidney injury.
Authors: Greite, Robert; Derlin, Katja; Hensen, Bennet; Thorenz, Anja; Rong, Song; Chen, Rongjun; Hellms, Susanne; Jang, Mi-Sun; Bräsen, Jan Hinrich; Meier, Martin; Willenberg, Ina; Immenschuh, Stephan; Haller, Hermann; Luft, Friedrich C; Panigrahy, Dipak; Hwang, Sung Hee; Hammock, Bruce D; Schebb, Nils Helge; Gueler, Faikah
Published In Am J Physiol Renal Physiol, (2020 10 01)
Abstract: Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.
PubMed ID: 32799675
MeSH Terms: Acute Kidney Injury/drug therapy*; Acute Kidney Injury/etiology; Acute Kidney Injury/pathology; Acute Kidney Injury/physiopathology; Angiotensin-Converting Enzyme Inhibitors/pharmacology; Animals; Antihypertensive Agents/pharmacology*; Antihypertensive Agents/toxicity; Blood Pressure/drug effects*; Disease Models, Animal; Disease Progression; Enalapril/pharmacology; Enzyme Inhibitors/pharmacology*; Enzyme Inhibitors/toxicity; Epoxide Hydrolases/antagonists & inhibitors; Fibrosis; Glomerular Mesangium/drug effects; Glomerular Mesangium/pathology; Glomerular Mesangium/physiopathology; Glomerulonephritis/etiology; Glomerulonephritis/pathology; Glomerulonephritis/physiopathology; Glomerulonephritis/prevention & control*; Hypertension/drug therapy*; Hypertension/etiology; Hypertension/physiopathology; Male; Mice; Phenylurea Compounds/pharmacology*; Phenylurea Compounds/toxicity; Piperidines/pharmacology*; Piperidines/toxicity; Reperfusion Injury/complications; Reperfusion Injury/drug therapy*; Reperfusion Injury/physiopathology