Name:
Kameswaran Ravichandran
Email:
[email protected]
Division:
Renal Diseases and Hypertension
Title:
Angiotensinogen inhibition slows polycystic kidney disease in mice with a targeted mutation in
Pkd2
Abstract:
Renal cyst enlargement is associated with the activation of both circulating and intra-renal renin-angiotensinaldosterone (RAAS) system. The aim of the study was to determine the effect of angiotensinogen inhibition in
polycystic kidney disease.
Methods:An Angiotensinogen antisense oligonucleotide (ASO) that selectively inhibits angiotensinogen (AGT)
mRNA was injected at 50mg/kg/wk dose i.p. once weekly in PKD2WS25mice (an orthologous model of human
ADPKD involving mutation of the Pkd2 gene) from 4 to 16 weeks of age.
Results: See Table. AGT protein was increased in blood and kidney in PKD and the AGT ASO resulted in a
significant decrease in AGT protein. The AGT ASO resulted in a significant decrease in kidney enlargement,
cyst volume density and BUN without an effect on body weight. The AGT ASO resulted in a significant
decrease in TGF-β and interstitial fibrosis (Sirius red staining) in the kidney. Mice treated with the AGT ASO
had a significant decrease in CXCL1, a neutrophil chemokine, and IL-12, a T cell stimulating factor, in the
kidney.
Conclusion: AGT inhibition decreases PKD, interstitial fibrosis and pro-inflammatory chemokines/cytokines and
represents a possible future therapy for ADPKD.
+/+ Scr ASO
(n=11) +/+
AGT ASO
(n=14) WS25
Scr ASO
(n=10) WS25
AGT ASO
(n=7)
BW (g)
28.2 ± 1.4 29.4 ± 0.1 27.3 ± 1.7
29.4 ± 2.2
2KW (g)
0.34 ± 0.02 0.35 ± 0.02 0.67 ± 0.06 * 0.47 ± 0.07 **
2K/TBW (%)
1.2 ± 0.03 1.2 ± 0.02 2.4 ± 0.2 *
1.5 ± 0.1 **
CVD (%)
0.4 ± 0.1
0.5 ± 0.4
34.1 ± 4.4 * 22 ± 2.9 **
BUN (mg/dL)
32 ± 3
29 ± 2
47± 5 +
34 ± 3 **
AGT protein
Serum (ng/mL)
2489 ± 625 1233 ± 523 3643 ± 496 * 1483 ± 353 **
AGT protein
Kidney (ng/mg) 1.3 ± 0.2
0.08 ± 0.06 6.1 ± 2*
0.7 ± 0.2 **
TGF-β (pg/mg)
53 ± 7
40 ± 8
102 ± 29*
32 ± 5*
Fibrosis score
0
0.4 ± 0.1*
0.1 ± 0.04**
CXCL1 (pg/mg) 0.4 ± 0.2
0.3 ± 0.1
3.4 ± 1
0.6 ± 0.2
IL-12
8±1
9±2
37 ± 16
9±2
*P<0.001 vs. +/+; ** P<0.001 vs. WS25 Scr ASO, NS vs +/+; BW=body weight, CVD=cyst volume density.
2K/TBW (%)=two kidney weight to total body weight ratio.
Research Category: Translational/"Bench to Bedside" Research

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