Purpose: Kidney fibrosis, a terminal pathway that is common among all CKD patients. Recent studies revealed that a reduction in nitric oxide (NO) is observed in the onset and progression of CKD and kidney fibrosis, and is related with a reduction in a production of erythropoietin (EPO) and an exacerbation of inflammation in the renal tissue, leading to aggravation of the fibrosis. These findings lead to the expectation that NO should exhibit therapeutic effects on kidney 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 kidney fibrosis was evaluated.

Methods: Using ICR mice, the left ureter was ligated as UUO model. The SNO-HSA, HSA or saline 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, in UUO mice. Also, SNO-HSA significantly suppressed histological changes such as the expansion of the fibrotic portions, the elevation in the expression of 8-OHdG, a oxidative 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 as the result of the SNO-HSA treatment. These results suggests that SNO-HSA suppressed kidney fibrosis through anti-inflammatory effect and increasing EPO level.

Conclusion: The present study demonstrated that SNO-HSA, a long-lasting NO donor, exerts anti-kidney fibrosis effects. Therefore, SNO-HSA has the potential to function as a therapeutic agent for the treatment of kidney fibrosis.