Characterization of Susceptibility of Inbred Mouse Strains to Diabetic Nephropathy
Article Figures & Tables
Figures
- FIG. 1.
Relationship between morning spot urine ACR and 24-h UAE in diabetic mice. Data were obtained from diabetic and control C57BL/6J (n = 4), DBA/2J (n = 6), and KK/HlJ (n = 9) mice. Spot urine was collected for 3 consecutive days from each mouse and average spot ACR was used for the correlation analysis. R2 = 0.69. P < 0.0001.
- FIG. 2.
Development of albuminuria in STZ-induced diabetic inbred mice after ∼25 weeks of hyperglycemia. A: Spot urine ACR in diabetic mice (▪) and age-matched controls (□). *P < 0.05 (t test) vs. respective age-matched controls; †P < 0.05 (ANOVA) vs. diabetic C57BL/6J, A/J, MRL/MpJ, and FVB/NJ mice; and ‡P < 0.001 (ANOVA) vs. controls in other strains. B: 24-h UAE in diabetic mice (▪) and age-matched controls (□). Age-matched controls for MRL/MpJ and FVB/NJ strains were not available (NA) for studying. *P < 0.05 (t test) vs. age-matched controls; §P < 0.05 (ANOVA) vs. diabetic C57BL/6J, A/J, and MRL/MpJ strains; and ‖P < 0.05 (ANOVA) vs. controls in other studied strains.
- FIG. 3.
Representative glomerular histopathology of perfuse-fixed diabetic mouse kidneys (periodic acid Schiff, ×400). A: C57BL/6J mice (35 weeks after STZ). B: A/J (32 weeks after STZ). C: MRL/MpJ (35 weeks after STZ). D: FVB/NJ (25 weeks after STZ). E: DBA/2J (25 weeks after STZ). F: Arteriolar hyalinosis (arrow) in diabetic DBA/2J mice. G: KK/HlJ mice (35 weeks after STZ). H: Nodular glomerulosclerosis (arrow) in diabetic KK/HlJ mice. I: Arteriolar hyalinosis (arrow) in diabetic KK/HlJ mice.
- FIG. 4.
Glomerular mesangial expansion scores in diabetic inbred mice. The scores were determined using light microscopy at ×400 in perfuse-fixed diabetic mouse kidneys as described in research design and methods. *P < 0.05 (t test) vs. age-matched controls; †P < 0.05 (ANOVA) vs. diabetic C57BL/6J, A/J, MRL/MpJ, and FVB/NJ mice; and ‡P < 0.05 vs. controls in other strains. Age-matched controls for diabetic FVB/NJ and MRL/MpJ were not available (NA).
- FIG. 5.
Electronic microscopic images of glomeruli from diabetic mice after 25 weeks (DBA/2J and FVB/NJ strains) to 35 weeks (C57BL/6J and KK/HlJ strains) of hyperglycemia. Opposed double arrows indicate GBM. E and M designate endothelial cell and mesangial cell, respectively.
- FIG. 6.
GBM width in diabetic inbred mice after ∼25 weeks of hyperglycemia (▪) and age-matched controls (□). *P < 0.05 (t test) vs. age-matched controls; †P < 0.05 (ANOVA) vs. diabetic C57BL/6J mice. The age-matched controls in FVB/NJ strain were not available (NA).
- FIG. 7.
Left kidney–to–body weight ratio in diabetic inbred mice after ∼25 weeks of hyperglycemia (▪) and age-matched controls (□). *P < 0.05 (t test) vs. age-matched controls; †P < 0.05 (ANOVA) vs. all studied strains of diabetic mice, and ‡P < 0.05 (ANOVA) vs. controls in other studied strains. The age-matched controls in FVB/NJ strain were not available.
- FIG. 8.
GFR in diabetic and age-matched control mice. *P < 0.05 vs. age-matched controls at same time point.
Tables
- TABLE 1
Fasting blood glucose and UAE in diabetic and control mice
Strain Glycemic status Before STZ Weeks after STZ or vehicle 5 15 25 C57BL/6J FBS (mg/dl) DM 170.0 ± 11.2 (10) 424.9 ± 33.9 (9)*† 502.5 ± 31.2 (21)*† 506.6 ± 46.0 (18)*† CN 170.0 ± 3.7 (10) 170.4 ± 7.1 (5) 164.8 ± 4.7 (5) 157.4 ± 8.1 (5) A1C (%) DM 3.8 ± 0.2 (3) NA 8.2 ± 0.4 (21)*† 9.4 ± 0.6 (11)*† CN 3.6 ± 0.1 (5) NA 4.1 ± 0.1 (5)* 3.8 ± 0.1 (5) BW (g) DM 21.3 ± 0.4 (10) 25.6 ± 0.6 (9)* 25.6 ± 0.7 (21)*† 26.9 ± 0.8 (18)* CN 20.3 ± 0.2 (5) 26.7 ± 1.2 (5)* 28.9 ± 0.9 (5)* 29.2 ± 1.4 (5)* ACR (μg/mg) DM 36.9 ± 7.6 (9) 35.4 ± 5.7 (9) 29.5 ± 12.4 (16)* 72.1 ± 20.4 (16) CN 45.6 ± 12.4 (5) 20.1 ± 1.6 (5) 48.11 ± 16.5 (5) 53.2 ± 24.3 (5) DBA/2J FBS (mg/dl) DM 160.5 ± 8.6 (15) 485.8 ± 31.3 (19)*† 485.3 ± 27.4 (21)*† 511.3 ± 75.6 (6)*† CN 165.2 ± 16.2 (5) 127.4 ± 15.5 (5)* 148.6 ± 8.5 (5) 152.6 ± 4.5 (5) A1C (%) DM 2.9 ± 0.1 (3) NA 6.7 ± 0.1 (21)*† 13.4 ± 0.8 (6)*†‡ CN 2.8 ± 0.1 (5) NA 2.8 ± 0.1 (5) 2.7 ± 0.2 (5) BW (g) DM 23.4 ± 0.6 (15) 22.3 ± 0.7 (19)† 20.8 ± 0.7 (21)*† 18.7 ± 0.9 (10)*† CN 22.2 ± 0.9 (6) 28.2 ± 0.8 (4)* 29.5 ± 1.2 (4)* 30.1 ± 0.9 (5)* ACR (μg/mg) DM 26.6 ± 6.6 (29) 424.4 ± 89.4 (24)*† 608.0 ± 220.8 (15)*†§ 421.4 ± 167.3 (11)*†§ CN 19.7 ± 5.1 (5) 48.7 ± 7.0 (9)* 71.1 ± 15.2 (7)* 65.8 ± 13.2 (7)* A/J FBS (mg/dl) DM 154.4 ± 4.4 (15) 360.8 ± 28.0 (10)*† 505.6 ± 31.4 (22)*† 391.6 ± 50.6 (16)*† CN 159.8 ± 7.8 (5) 146.0 ± 13.4 (4) 157.0 ± 4.0 (4) 171.0 ± 2.1 (4) A1C (%) DM 2.6 ± 0.03 (9) NA 5.1 ± 0.1 (22)*†¶ 4.1 ± 0.2 (16)*†¶ CN 2.6 ± 0.03 (5) NA 2.6 ± 0.04 (5) 2.6 ± 0.04 (5) BW (g) DM 23.4 ± 0.6 (15) 18.3 ± 0.6 (10)*† 20.5 ± 0.8 (27)*† 23.2 ± 0.7 (16)† CN 22.9 ± 0.6 (5) 26.8 ± 0.8 (4)* 28.2 ± 0.9 (4)* 30.6 ± 1.3 (5)* ACR (μg/mg) DM 26.6 ± 12.2 (23) 119.5 ± 21.1 (27)* 174.0 ± 48.2 (17)*† 64.0 ± 12.6 (15)* CN 18.7 ± 2.2 (5) 54.5 ± 14.2 (5)* 88.4 ± 25.8 (4)* 81.2 ± 8.8 (4)* FVB/NJ FBS (mg/dl) DM 141.8 ± 12.4 (12) 576.0 ± 43.0 (8)*† 549.4 ± 52.1 (10)*† 610.0 ± 23.3 (5)*† CN 134.0 ± 19.8 (4) 169.5 ± 2.5 (4) 148.3 ± 19.8 (4) 151.0 ± 12.1 (4) A1C (%) DM 3.0 ± 0.1 (7) NA 5.8 ± 0.2 (10)*† 5.0 ± 0.3 (5)* CN NA NA 3.0 ± 0.2 (4) NA BW (g) DM 27.9 ± 0.8 (12) 26.8 ± 0.3 (8) 27.4 ± 0.6 (10) 33.0 ± 0.5 (5)* CN 26.7 ± 2.0 (4) 29.0 ± 2.2 (4) 30.0 ± 2.1 (4) 33.1 ± 1.8 (4) ACR (μg/mg) DM 61.6 ± 13.2 (7) 6.1 ± 1.4 (9)*† 88.0 ± 21.3 (12) 89.3 ± 27.7 (7) CN 45.4 ± 18.5 (4) 74.1 ± 21.7 (4) NA 63.0 ± 31.0 (4) MRL/MpJ FBS (mg/dl) DM 120.8 ± 6.6 (5) 434.8 ± 22.7 (19)*† 493.5 ± 21.9 (17)*† 428.0 ± 45.1 (5)*† CN 140.5 ± 4.8 (4) 165.0 ± 3.7 (4) 155.0 ± 12.4 (4) 153.5 ± 20.2 (4) A1C (%) DM 3.0 ± 0.1 (5) 5.3 ± 0.1 (19) 6.9 ± 0.2 (8)*† 6.1 ± 0.2 (5)*† CN 3.0 ± 0.1 (4) NA 3.6 ± 0.2 (4) 3.3 ± 0.4 (4) BW (g) DM 37.1 ± 0.4 (5) 34.0 ± 0.8 (19)* 36.7 ± 0.6 (17) 37.0 ± 1.4 (5) CN 35.7 ± 1.4 (4) 36.5 ± 2.6 (4) 38.6 ± 3.7 (4) 39.2 ± 4.3 (4) ACR (μg/mg) DM 74.4 ± 17.0 (14) 95.2 ± 43.4 (20) 122.5 ± 32.7 (18)† 87.7 ± 22.3 (6)† CN 39.5 ± 14.2 (4) 73.2 ± 14.5 (4) 18.0 ± 7.5 (4) 43.2 ± 14.0 (4) KK/HlJ FBS (mg/dl) DM 160.6 ± 7.4 (15) 297.5 ± 30.6 (15)*†‖ 321.3 ± 23.0 (19)*†‖ 330.0 ± 32.8 (13)*†‖ CN 142.0 ± 5.2 (5) 157.4 ± 9.3 (10) 158.8 ± 6.8 (10) 156.8 ± 10.9 (10) A1C (%) DM 4.5 ± 0.1 (15)† NA 6.4 ± 0.4 (19)*† 6.4 ± 0.5 (13)*† CN 4.7 ± 0.2 (5) NA 4.8 ± 0.2 (10) 4.0 ± 0.1 (8)* BW (g) DM 31.4 ± 1.0 (25) 29.8 ± 0.7 (15) 30.9 ± 0.6 (19)† 32.3 ± 0.8 (13)† CN 31.4 ± 1.5 (7) 33.8 ± 1.5 (5) 36.6 ± 1.4 (10)* 35.9 ± 1.1 (13)* ACR (μg/mg) DM 72.9 ± 12.1 (13) 509.9 ± 87.6 (19)*† 586.9 ± 84.9 (19)*†§ 635.8 ± 122.0 (13)*†§ CN 72.8 ± 11.4 (14) 177.0 ± 50.7 (10) 224.4 ± 80.8 (10)* 349.1 ± 39.7 (10)* Data are means ± SE (no. of animals).
- *
* P < 0.05 vs. baseline at same group;
- †
† P < 0.05 vs. age-matched controls at same time point;
- ‡
‡ P < 0.05 vs. all other diabetic strains at same time point;
- §
§ P < 0.05 vs. diabetic C57BL/6J, A/J, FVB/NJ, and MRL/MpJ mice;
- ¶
¶ P < 0.001 vs. A1C in all other diabetic strains except FVB/NJ strain at same time point;
- ‖
‖ P < 0.05 vs. FBS in diabetic C57BL/6J, DBA/2J, and FVB/NJ mice at same time point. BW, body weight; CN, control mice; DM, diabetic mice; FBS, fasting blood glucose; NA, not available.
- TABLE 2
Temporal pattern of GFR in STZ-induced diabetic and control inbred mice
Strain Before STZ Weeks after STZ or vehicle 5 15 25 C57BL/6J Diabetic 217.2 ± 13.7 (18) 300.6 ± 24.2 (13)* 275.4 ± 31.7 (12)* 345.5 ± 24.5 (9)* Control 207.5 ± 18.7 (12) 306.0 ± 47.2 (8)* 244.3 ± 37.9 (4) 325.9 ± 17.6 (5)* DBA/2J Diabetic 220.6 ± 22.7 (20) 365.5 ± 30.4 (23)* 451.9 ± 62.8 (8)* 369.9 ± 43.0 (12)*† Control 246.3 ± 35.1 (8) 457.5 ± 23.2 (3)* 452.2 ± 121.5 (3)* 473.9 ± 29.4 (12)* A/J Diabetic 261.2 ± 23.6 (16) 246.7 ± 27.3 (15)† 288.7 ± 20.6 (10)† 287.5 ± 28.6 (15) Control 271.5 ± 47.4 (4) 378.5 ± 32.8 (4) 393.6 ± 13.8 (4) 301.0 ± 80.6 (4) FVB/NJ Diabetic 254.4 ± 26.3 (16) 479.3 ± 64.8 (11)* 562.8 ± 40.0 (4)*† 822.6 ± 84.9 (7)*‡§ Control 260.2 ± 43.9 (7) 245.7 ± 58.8 (4) 302.4 ± 15.2 (4) NA MRL/MpJ Diabetic 239.8 ± 72.9 (7) 309.6 ± 36.2 (14) 491.5 ± 69.3 (8)*‡ 479.1 ± 49.9 (7)*†‡ Control 300.3 ± 118.6 (4) NA 302.3 ± 31.7 (4) 272.3 ± 25.6 (4) KK/HlJ Diabetic 269.3 ± 28.9 (12) 353.6 ± 24.6 (17)* 285.6 ± 19.5 (15)‡† 315.4 ± 37.2 (10) Control 261.4 ± 32.6 (8) 286.0 ± 26.8 (4) 483.0 ± 64.6 (6)*‡ 307.7 ± 39.3 (17)§ Data are means ± SE (μl/min) (no. of animals). NA, not available.
- *
* P < 0.05 vs. GFR before STZ injection;
- †
† P < 0.05 vs. controls at same time point;
- ‡
‡ P < 0.05 vs. GFR at 5 weeks after STZ;
- §
§ P < 0.05 vs. GFR at 15 weeks after STZ.
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