Shun Oshiro¹, Yu Ishima², Hitoshi Maeda¹, Hiroshi Watanabe¹, Masaki Otagiri³, Toru Maruyama¹

¹Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan

²Department of Pharmacokinetics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokushima University, Japan

³Faculty of Pharmaceutical Sciences, Sojo University, Japan

Corresponding author: tomaru@gpo.kumamoto-u.ac.jp.

ABSTRACT

Background and Objective:Renal fibrosis is a common pathway among all Chronic kidney disease (CKD) patients. Recent studies revealed that a reduction in nitric oxide (NO) is observed in the onset and progression of CKD and renal fibrosis, and is related with a reduction in a production of erythropoietin (EPO) and an exacerbation of inflammation, leading to aggravation of the fibrosis. These findings lead to the expectation that NO should exhibit therapeutic effects on renal fibrosis. However, the biological half-life of NO is extremely short which limits its clinical application, therefore we created S-nitrosated human serum albumin (SNO-HSA). In the present study, the therapeutic effect of SNO-HSA on renal fibrosis was evaluated. Materials and Methods:Using ICR mice, the left ureter was ligated as unilateral ureteral obstruction (UUO) model. The SNO-HSA was administered intravenously just after the ligation (Day 0) and two days afterward (Day 2). Mice were sacrificed on Day 7 or Day 14 after surgery. Results:On Day 14, the SNO-HSA treatment significantly reduced an increase in hydroxyproline and α-SMA, fibrosis markers. Also, SNO-HSA significantly suppressed histological changes such as the expansion of the fibrotic portions, the elevation in the expression of 8-OHdG, anoxidative stress marker, and the reduction in that of CD31, a vascular endothelial cells marker. In the UUO model, fibrosis progresses rapidly before Day 7, therefore, the point of evaluation was changed from Day 14 to Day 7. SNO-HSA significantly suppressed elevations in mRNA levels of α-SMA, TGF-β and IL-6 as profibrotic factors. Also, the levels of EPO mRNA in kidneys of UUO-treated mice were markedly increased by the SNO-HSA treatment. Conclusion:The present study demonstrated that SNO-HSA, a long-lasting NO donor, exerts anti-renal fibrosis effects via anti-inflammatory effect and increased EPO level.