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Sustained-release prostacyclin analog ONO-1301 ameliorates tubulointerstitial alterations in a mouse obstructive
Tatsuyo Nasu1, Masaru Kinomura, Katsuyuki Tanabe
1Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Abstract:
Tubulointerstitial injuries are crucial histological alterations that predict the deterioration of renal function in chronic kidney disease. ONO-1301, a novel sustained-release prostacyclin analog, accompanied by thromboxane synthase activity, exerts therapeutic effects on experimental pulmonary hypertension, lung fibrosis, cardiomyopathy, and myocardial ischemia, partly associated with the induction of hepatocyte growth factor (HGF). In the present study, we examined the therapeutic efficacies of ONO-1301 on tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO). After inducing unilateral ureteral obstruction in C57/BL6J mice, a single injection of sustained-release ONO-1301 polymerized with poly (D,L-lactic-co-glycolic acid) sustained-release ONO-1301 (SR-ONO) significantly suppressed interstitial fibrosis, accumulation of types I and III collagen, increase in the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) cells, and interstitial infiltration of monocytes/macrophages (F4/80(+)) in the obstructed kidneys (OBK; day 7). Treatment with SR-ONO significantly suppressed the increase of the renal levels of profibrotic factor TGF-β and phosphorylation of Smad2/3, and elevated the renal levels of HGF in the OBK. In cultured mouse proximal tubular epithelial cells (mProx24), ONO-1301 significantly ameliorated the expression of fibroblast-specific protein-1 and α-smooth muscle actin as well as phosphorylation of Smad3 and increased the expression of zonula occludens-1 and E-cadherin in the presence of TGF-β1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI(2) receptor-mediated signaling. Administration of rabbit anti-HGF antibodies, but not the control IgG, partly reversed the suppressive effects of SR-ONO on tubulointerstitial injuries in the OBK. Taken together, our findings suggest the potential therapeutic efficacies of ONO-1301 in suppressing tubulointerstitial alterations partly mediated via inducing HGF, an antifibrotic factor counteracting TGF-β.
Insights
Sustained-release ONO-1301 effectively treats kidney injury by reducing fibrosis and inflammation. This prostacyclin analog induces hepatocyte growth factor (HGF), counteracting profibrotic factors like TGF-β.
Area of Science:
- Nephrology
- Pharmacology
- Fibrosis Research
Background:
- Tubulointerstitial injuries are key indicators of chronic kidney disease progression.
- ONO-1301, a prostacyclin analog, shows therapeutic potential via hepatocyte growth factor (HGF) induction.
- Unilateral ureteral obstruction (UUO) is a model for studying kidney injury and fibrosis.
Purpose of the Study:
- To investigate the therapeutic effects of ONO-1301 on tubulointerstitial alterations in a mouse model of UUO.
- To explore the underlying mechanisms, including HGF induction and modulation of fibrotic pathways.
Main Methods:
- UUO was induced in C57/BL6J mice, followed by administration of sustained-release ONO-1301 (SR-ONO).
- Kidney tissues were analyzed for interstitial fibrosis, collagen deposition, cell infiltration, and expression of fibrotic markers (TGF-β, Smad2/3).
- In vitro studies used cultured mouse proximal tubular cells to assess ONO-1301's effects on specific protein expression and signaling pathways.
Main Results:
- SR-ONO significantly suppressed interstitial fibrosis, collagen accumulation, and inflammatory cell infiltration in obstructed kidneys.
- Treatment reduced renal TGF-β levels and Smad2/3 phosphorylation while increasing HGF levels.
- In vitro, ONO-1301 ameliorated fibrotic markers and restored epithelial integrity, partly via PGI2 receptor signaling.
Conclusions:
- ONO-1301 demonstrates significant therapeutic potential in mitigating tubulointerstitial injuries caused by UUO.
- The drug's efficacy is partly mediated by the induction of HGF, an antifibrotic factor that counteracts TGF-β signaling.
- Findings suggest ONO-1301 as a potential treatment for chronic kidney disease characterized by tubulointerstitial fibrosis.
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