Inhibition of connective tissue growth factor by small interfering RNA prevents renal fibrosis in rats undergoing
1Transplantation Institute, West China Hospital, Sichuan University, Chengdu, China.
Aim:
Connective tissue growth factor (CTGF) is a highly profibrogenic molecule implicated in renal fibrogenesis. Small interfering RNA (siRNA) is an effective tool to silence gene expression. This study determined whether caudal vein injection of siRNA targeting CTGF inhibited its expression in rat kidneys in vivo, and furthermore whether it protected the kidney from renal fibrosis in chronic allograft nephropathy (CAN).
Methods:
Male inbred Fischer (F344, RT1(lv1)) rat renal grafts were orthotopically transplanted into Lewis (LEW, RT1(1)) rats following the procedure of Kamada with our modification. At 6 weeks, recipients were divided into siRNA, normal saline (NS), and control siRNA groups, using daily siRNA-targeting CTGF (0.1 mg/kg), or NS, or a control siRNA via caudal vein injection for 14 days. At 4, 6, and 8 weeks, we observed the pathologic changes, expression of CTGF, E-cadherin, collagen I and IV, and anti-smooth muscle actin (alpha-SMA).
Results:
Serum creatinine level, Banff score, and the expression of CTGF were significantly lower among the siRNA than the NS or the control siRNA groups at 8 weeks (P < .05). The expressions of collagen I and IV, and alpha-SMA were also significantly downregulated and E-cadherin was lost in the siRNA versus the NS and control siRNA groups at 8 weeks.
Conclusions:
This study showed that delivery of CTGF siRNA via the caudal vein significantly inhibited expression of CTGF in rat kidneys, effectively preventing fibrosis in CAN. The results suggest that siRNA-targeting of CTGF has the potential to be a novel strategy for amelioration of CAN.
Insights
Small interfering RNA (siRNA) targeting connective tissue growth factor (CTGF) effectively reduced kidney fibrosis in rats with chronic allograft nephropathy (CAN). This CTGF siRNA therapy shows promise for treating kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Connective tissue growth factor (CTGF) is a key driver of kidney fibrosis.
- Chronic allograft nephropathy (CAN) is a significant complication of kidney transplantation.
- Small interfering RNA (siRNA) offers a method to silence specific gene expression.
Purpose of the Study:
- To investigate if caudal vein injection of CTGF-targeting siRNA can inhibit CTGF expression in rat kidneys.
- To determine if this inhibition protects against renal fibrosis in a rat model of CAN.
Main Methods:
- Orthotopic renal transplantation in a rat model of CAN.
- Daily caudal vein injection of CTGF siRNA, normal saline, or control siRNA for 14 days.
- Assessment of pathological changes and molecular markers (CTGF, E-cadherin, collagen I/IV, alpha-SMA) at various time points.
Main Results:
- CTGF siRNA treatment significantly reduced serum creatinine and Banff scores compared to control groups.
- Expression of CTGF, collagen I/IV, and alpha-SMA was significantly downregulated in the CTGF siRNA group.
- E-cadherin expression was lost in the control groups but preserved in the CTGF siRNA group.
Conclusions:
- Caudal vein delivery of CTGF siRNA effectively inhibits CTGF expression in rat kidneys.
- This approach significantly ameliorates renal fibrosis in CAN.
- Targeting CTGF with siRNA represents a potential novel therapeutic strategy for CAN.
