Abstract
Objective: Losartan was reported to inhibit the progression of acute kidney injury (AKI), but little is known about the underlying pharmacological mechanisms. In the present study, the mRNA expression profiles in ischemic AKI rat kidney altered by losartan treatment were analyzed by next-generation deep sequencing technology.Methods: Ischemia and reperfusion treatment was applied to induce AKI in Sprague–Dawley (SD) rats. The urea and creatinine contents in rat blood were measured. H&E staining was performed to evaluate the histological alteration of rat kidney tissues under a microscope. The TUNEL method was applied to analyze apoptosis in rat kidney tissues. The mRNA profiles in rat kidney were analyzed using next-generation deep sequencing. Differential gene expression was confirmed by quantitative qRT-PCR.Results: The rat model of AKI induced by ischemia and reperfusion showed significant increases in urea and creatinine levels, accompanied by a disrupted kidney tubular structure and renal cell apoptosis. Losartan treatment effectively inhibited the changes in urea and creatinine, tubular structure, and apoptosis in AKI rat kidney. A large number of mRNAs were found to be differentially expressed in the kidneys of AKI rats treated with losartan, which are involved in multiple processes and signaling pathways. The expression of nine differentially expressed genes such as monocyte chemoattractant protein-1 (CCL2) and suppressor of cytokine signaling 3 (SOCS3) was confirmed by qRT-PCR and Western blot.Conclusion: Losartan caused significant alterations in the gene expression profile in AKI rat kidney, which mediated its anti-AKI effects.
Highlights
Acute kidney injury (AKI), known as acute renal failure, is a common disease involving severe nephropathy featuring the characteristic of sudden dysfunction of the kidneys, which often develops in less than a week [1,2]
Using the TUNEL method, we found that ischemia and reperfusion induced a significant increase in apoptotic renal cells in rat kidney tissues associated with AKI, in comparison with the level in the sham group (Figure 1D)
We found that the expression levels of monocyte chemoattractant protein-1 (CCL2), Heme oxygenase 1 (HMOX1), suppressor of cytokine signaling 3 (SOCS3), and Glycoprotein non-metastatic b (GPNMB) were significantly elevated in rats after the induction of AKI by ischemia and reperfusion; their levels were remarkably suppressed by the treatment with losartan in rat kidney tissues (Figure 5A–C,E)
Summary
Acute kidney injury (AKI), known as acute renal failure, is a common disease involving severe nephropathy featuring the characteristic of sudden dysfunction of the kidneys, which often develops in less than a week [1,2]. Losartan is one of the effective inhibitors of angiotensin II (ANG II) type 1 receptors (AT1), which was approved for clinical usage in 1995. It has been widely used in the clinical management of various human disorders including diabetic kidney disease, high blood pressure, and multiple cardiac diseases such as acute myocardial infarction (AMI) [12,13,14]. Extensive investigations have revealed multiple mechanisms underlying the therapeutic effects of losartan, including the inhibition of sensitivity of the human organs to ANG II, promotion of the activity of plasma renin, the decrease in aldosterone release, and the suppression of uric acid uptake [15]
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