Table 2.
Src inhibition in PCK: Morphometrics and functional parameters
| Parameter | SD
|
PCK
|
||
|---|---|---|---|---|
| Untreated(n = 10) | SKI-606(n = 10) | Untreated(n = 15) | SKI-606(n = 15) | |
| Body weight (g) | 335.00 ± 22.00 | 330.00 ± 18.00b | 387.60 ± 40.00c | 375.00 ± 18.00 |
| Kidney weight (g) | 2.40 ± 0.30 | 2.30 ± 0.40b | 5.90 ± 0.80c | 4.10 ± 0.60g |
| Kidney weight/body weight (%) | 0.70 ± 0.10 | 0.70 ± 0.10b | 1.50 ± 0.10c | 1.10 ± 0.30f |
| PN90 renal cystic volume | 0.00 ± 0.00 | 0.00 ± 0.00 | 30.90 ± 11.00c | 14.80 ± 7.00g |
| PN90 liver weight/body weight (%) | 3.50 ± 0.40 | 3.40 ± 0.40 | 4.80 ± 0.70e | 4.00 ± 0.60f |
| BUN (mg/dl) | 16.00 ± 1.50 | 17.00 ±1.20b | 36.00 ± 2.80c | 23.00 ± 1.40g |
| Creatinine (mg/dl) | 0.22 ± 0.10 | 0.22 ± 0.10b | 0.59 ± 0.40c | 0.36 ± 0.30g |
| Renal cAMP pmol/mg protein | 7.72 ± 0.30 | 7.49 ± 0.30 | 13.63 ± 1.00c | 13.23 ± 1.00 |
| Max urinary concentrating 12 h | 1315.00 ± 44.00 | 1299.00 ± 55.00b | 949.00 ± 108.00d | 1087.00 ± 153.00e |
Data are means ± SD. Results demonstrate that cystic animals treated with SKI-606 (n = 15) showed a 27% (P < 0.02) reduction in kidney weight/body weight ratio, reduction in renal cyst volume of 52% (P < 0.001), and a 17% decrease in LW/body weight ratios (P < 0.02) compared with untreated cystic animals (n = 15). Renal functional parameters also demonstrated improvement with SKI-606 treatment. BUN levels decreased 36% (P < 0.001), creatinine levels decreased by 45% (P < 0.001), and maximum urinary concentrating ability increased by 12% (P < 0.05). A particularly striking result was the lack of change in renal cAMP levels in the PCK after Src inhibition. This suggests that the effect of Src inhibition in the aberrant signal transduction pathway of ARPKD occurs below the level of cAMP. This also suggests that amelioration of renal cystic changes can occur without reduction of renal cAMP. Treatment of Sprague-Dawley controls demonstrated no significant differences in assessed parameters compared with untreated controls.
NS, Sprague-Dawley untreated versus Sprague-Dawley treated (SKI-606).
P < 0.01,
P < 0.02,
P < 0.05, Sprague-Dawley untreated versus PCK untreated.
P < 0.02,
P < 0.01, PCK treated (SKI-606) versus PCK untreated.