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Published on: May 10, 2022
Small interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury
Péter Hamar1, Erwei Song, Gabor Kökény
1Institute of Pathophysiology, Semmelweis University, Nagyvárad tér 4, Budapest, H 1089, Hungary. hampet@net.sote.hu
Abstract:
Fas-mediated apoptosis has been suggested to contribute to tubular cell death after renal ischemia-reperfusion injury. Here we investigate whether small interfering RNA (siRNA) duplexes targeting Fas protect mice from acute renal failure after clamping of the renal artery. Renal ischemia-reperfusion injury was induced by clamping the renal vein and artery for 15 or 35 min. Mice were treated before or after ischemia with siRNA targeting Fas or a control gene, administered by hydrodynamic injection, low-volume renal vein injection, or both. Treated mice were evaluated for renal Fas protein and mRNA expression, tissue histopathology, and apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining. Blood urea nitrogen and survival were monitored in mice in which the contralateral kidney had been removed. A single hydrodynamic injection of Fas siRNA reduced Fas mRNA and protein expression in the kidney 4-fold. Kidneys from mice that received Fas siRNA two days earlier had substantially less renal tubular apoptosis by TUNEL staining and less tubular atrophy and hyaline damage. Whereas 90% of mice pretreated with saline or GFP siRNA died, only 20% of Fas-siRNA-pretreated animals died. The same survival advantage was provided by a single low-volume Fas siRNA injection into the renal vein. Moreover, postischemic injection through the renal vein protected 38% of mice from death. This study confirms the importance of Fas-mediated apoptosis in renal ischemia-reperfusion injury. Silencing Fas by systemic or local catheterization holds therapeutic promise to limit ischemia-reperfusion injury.
Insights
Small interfering RNA (siRNA) targeting Fas significantly reduced kidney damage and improved survival in mice after renal ischemia-reperfusion injury. This approach offers a promising therapeutic strategy for acute kidney injury.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Fas-mediated apoptosis is implicated in tubular cell death following renal ischemia-reperfusion injury (RIRI).
- Investigating therapeutic interventions to mitigate RIRI is crucial for patient outcomes.
Purpose of the Study:
- To determine if small interfering RNA (siRNA) targeting Fas can protect mice against acute renal failure induced by RIRI.
- To evaluate the efficacy of different administration methods for Fas-targeting siRNA.
Main Methods:
- Renal ischemia-reperfusion injury was induced in mice by clamping the renal artery.
- Mice received Fas siRNA or control siRNA via hydrodynamic injection, renal vein injection, or both, before or after ischemia.
- Kidney tissue was analyzed for Fas expression, apoptosis (TUNEL staining), and histopathology.
- Survival and blood urea nitrogen levels were monitored in nephrectomized mice.
Main Results:
- A single hydrodynamic injection of Fas siRNA reduced kidney Fas mRNA and protein expression by fourfold.
- Fas siRNA treatment led to significantly less tubular apoptosis, atrophy, and hyaline damage.
- Survival rates increased dramatically in Fas siRNA-treated mice (80% survival) compared to controls (10% survival).
- Both systemic and local administration of Fas siRNA provided a survival advantage, with postischemic injection protecting 38% of mice.
Conclusions:
- Fas-mediated apoptosis plays a critical role in RIRI.
- Silencing Fas using siRNA, delivered systemically or locally, demonstrates significant therapeutic potential for limiting RIRI and improving survival.
- This strategy holds promise for clinical application in managing acute kidney injury.
