RENAL FUNCTION AND STRUCTURE IN DIABETIC, HYPERTENSIVE, OBESE ZDFxSHHF-HYBRID RATS

Figures & data

Figure 1. Blood pressure in 46 weeks old ZDFxSHHF, SHHF, SHR and WKY rats (1-F Anova, p < 0.05; a - vs SHR and WKY).

Table 1. Heart weights and heart performance in vivo in 11 months old WKY, SHR, SHHF/Mcc-fa^cp and ZDFxSHHF-hybrid rats

Parameters	WKY	SHR	SHHF	ZDFxSHHF
(M ± SE)	(n = 8)	(n = 6)	(n = 6)	(n = 6)
Heart weight (g)	1.66 ± 0.06	1.75 ± 0.06	2.01 ± 0.15^d	2.19 ± 0.11^a
Heart/B.W. (mg/g)	2.57 ± 0.09	4.31 ± 0.20^d	3.03 ± 0.25^e	3.41 ± 0.39^a
Heart/brain ratio	0.83 ± 0.03	1.06 ± 0.06	1.17 ± 0.07^d	1.21 ± 0.06^a
Heart rate (b/min)	345 ± 14.6	379 ± 10.3	358 ± 15.8	349 ± 9.3
VPSP (mmHg)	125.5 ± 4.4	252 ± 15.8^d	195 ± 15.3^a	169.8 ± 17.7^a
+dP/dtmax (mmHg sec^−1)	7651 ± 1319	13551 ± 1505^d	11219 ± 1068	10153 ± 2074
−dP/dtmax (mmHg sec^−1)	4642 ± 756	10103 ± 599	7690 ± 1217	5200 ± 1258^e
+dP/dtmax/P (sec^−1)	355.3 ± 87.6	352.7 ± 62.5	223.5 ± 38.3	221.5 ± 28.8
VEDP (mmHg)	6.90 ± 1.87	2.98 ± 2.42	10.85 ± 3.77^e	7.12 ± 2.30
VMDP (mmHg)	−1.90 ± 1.79	−9.23 ± 4.04	−4.55 ± 3.33	−2.06 ± 0.94

VPSP = ventricular peak systolic pressure

+dP/dt_max = maximum dP/dt during ventricular contraction

−dP/dt_max = maximum dP/dt during the ventricular contraction

VEDP = ventricular end diastolic pressure

VMDP = ventricular minimum diastolic pressure

1-F ANOVA; p < 0.05

a = vs. WKY and SHR

b = vs. SHR and SHHF/Mcc-fa^cp

c = vs. WKY and SHHF/Mcc-fa^cp

d = vs. WKY

e = vs. SHR.

Figure 2. Metabolic status in 46 weeks old ZDFxSHHF, SHHF, SHR and WKY rats. (1-F Anova, p < 0.05; a - vs SHR and WKY; b - vs all other groups).

Table 2. Metabolic and renal function in 11 months old WKY, SHR, SHHF/Mcc-fa^cp and ZDFxSHHF-hybrid rats

Parameters	WKY	SHR	SHHF	ZDFxSHHF
(M ± SE)	n = 8	n = 6	(n = 6)	(n = 11)
Body weight (g)	645 ± 14.4	407 ± 9.5^c	672 ± 39.8	653.6 ± 45.8
Food intake (g/kg/day)	41.7 ± 1.3	51.4 ± 2.1	40.6 ± 3.9	35.1 ± 3.6^b
Fluid intake (ml/kg/day)	73.0 ± 5.9	109.8 ± 7.7	108.2 ± 14.6^a	138.2 ± 13.5^a
Urine volume (ml/kg/day)	46.0 ± 7.6	47.3 ± 6.4	81.1 ± 16.2	125.0 ± 12.7^a
Na + excretion (mEq/kg/day)	3.51 ± 0.25	3.33 ± 0.26	3.18 ± 0.36	3.37 ± 0.37
K + excretion (mEq/kg/day)	10.5 ± 0.56	10.5 ± 0.88	9.6 ± 0.87	8.1 ± 0.83
Plasma Creatinine (mg/dl)	0.66 ± 0.03	0.97 ± 0.07^*	1.03 ± 0.3	3.62 ± 0.59^a7∮
Creatinine Clearance (L/kg/day)	5.73 ± 0.34	3.89 ± 0.39^*	2.41 ± 0.78^a	0.67 ± 0.12^a7∮
Urinary protein excretion UPE (mg/kg/day)	44.5 ± 7.6	109.0 ± 21.0^*	2335 ± 427^a	1668 ± 208^a7∮
UPE/Kidney (mg/g kidney/day)	23.4 ± 4.0	75.2 ± 14.5^*	1179 ± 215^a	536.3 ± 66.9^a7∮
UPE/Creatin Clearance (mg/L)	7.8 ± 1.32	29.8 ± 5.4^*	1297 ± 171^a	1939 ± 310^a7∮

1F-ANOVA (p < 0.05)

a = vs. WKY and SHR

b = vs. SHR

c = vs. all other groups student “t” (p < 0.05)

∮ = vs. SHHF/Mcc-fa^cp

^* = vs. WKY.

Figure 3. Obese 46 weeks old male ZDFxSHHF rat - Low power magnification of superficial through deep renal cortex showing prominent dilated tubules containing proteinaceous fluid, and many abnormal glomeruli (methenamine silver-trichrome (A)(MST), 26x). Abnormal glomeruli at higher magnification (B) showing segmental collapse/sclerosis (MST, 257x), and global collapse/mesangial expansion with hypertrophied podocytes containing protein resorption droplets (arrow) (c) (MST, 257x).

Table 3. Kidney weight and renal hystology in 46 weeks old male, WKY, SHR, SHHF and ZDFxSHHF-hybrid rats

	WKY	SHR	SHHF	ZDFxSHHF
	n = 6	n = 6	n = 9	n = 11
Kidney (gr)	1.90 ± 0.05	1.45 ± 0.09^¶	1.98 ± 0.14	3.11 ± 0.14^¶
Kidney/body weight (mg/g)	2.95 ± 0.08	3.67 ± 0.16^†	2.94 ± 0.11	4.75 ± 0.45^x, ‡
Kidney/Brain weight ratio	0.96 ± 0.02	0.98 ± 0.09	1.16 ± 0.07	1.71 ± 0.09^x, ‡
FSGS + FGGS (%)	0	1.1 ± 0.5	33.2 ± 3.0^x	59.2 ± 6.9^x, ‡
Tubular Atrophy (0-3^+)	0	0	1.45 ± 0.17^a	2.3 ± 0.2^a,**
Tubular Dilatation (0-4^+)	0.08 ± 0.07	1.0 ± 0^*	3.4 ± 0.12^a	3.3 ± 0.15^a
Cast (0-3^+)	0.08 ± 0.07	1.0 ± 0^*	3.4 ± 0.1^a	3.2 ± 0.2^a
Interst. Inflammation (0-3^+)	0	0	1.85 ± 0.28^a	2.3 ± 0.2^a
Interstitial Fibrosis (0-3^+)	0	0	1.25 ± 0.1^a	2.7 ± 0.2^a, ^**
Medial Hytpertrophy (0-3^+)	0.25 ± 0.16	1.6 ± 0.19^*	2.35 ± 0.27^a	2.4 ± 0.2^a
Arteriolar Sclerosis (0-3^+)	0	1.5 ± 0.16^*	2.1 ± 0.28^a	2.6 ± 0.2^a

1F-ANOVA (p < 0.05)

x = vs. WKY and SHR

¶ = vs. all other groups; student “t” test (p < 0.05)

† = vs. WKY

‡ = vs. SHHF; Mann-Whitney test (p < 0.05)

a = vs. WKY and SHR

^* = vs. WKY

^** = vs. SHHF.

Table 4. Metabolic profile of 29 weeks old obese (fa/fa^cp) and lean (+/fa, +/+) ZDF-SHHF-hybrid rats

Parameters	Lean (n = 6)	Obese (n = 7)
Body Weight (g)	503.3 ± 12.0	614 ± 17.9^*
Food Intake (g/kg/day)	48.0 ± 2.1	63.0 ± 3.3^*
Fluid Intake (mL/kg/day)	69.4 ± 2.9	153.9 ± 19.0^*
Glucose (mg/dL)	115.0 ± 10.9	424.0 ± 37.1^*
Insulin (μU/mL)	42.3 ± 3.5	117.2 ± 8.8^*
Triglycerides (mg/dL)	194.3 ± 23.4	5200 ± 702^*
Total Cholesterol (mg/dL)	109 ± 4.1	632.1 ± 38.9^*
HDL-Chol (mg/dL)	48.2 ± 2.3	68.1 ± 12.2^*
VLDL + LDL-Chol	61.4 ± 3.0	464.1 ± 41.8^*

^* p < 0.05 two groups “t” test.

Figure 4. Obese 29 weeks old male ZDFxSHHF rat - Low power magnification of superficial through mid renal cortex showing focally dilated tubules containing proteinaceous material and scattered abnormal glomeruli (A) (MST, 26x). At higher magnification, there is a spectrum of glomerular pathology ranging from mild mesangial matrix expansion (arrow) to marked mesangial and segmental sclerosis (arrowhead) (B) (MST, 129x).

Figure 5. Lean 29 weeks old male ZDFxSHHF rat - Low power magnification of entire renal cortex through superficial medulla showing no discernible abnormality (A) (MST, 26x). At higher magnification, glomeruli show mild diffuse mesangial matrix expansion (B) (MST, 129x).

Table 5. Hemodynamic and renal function parameters in anesthetized (A) and conscious (B), 29 weeks old obese (fa/f^cp) and lean (+/fa, +/+) ZDF-SHHF-hybrid rats; ^* p < 0.05

Parameters	Lean (n = 6)	Obese (n = 7)
A
Mean Arterial Blood Pressure (mmHg)	164.7 ± 2.0	165.3 ± 5.2
Heart Rate (b/min)	367 ± 11.9	348 ± 11.9
Renal Blood Flow (mL/g kid/min)	8.68 ± 0.63	3.44 ± 0.35^*
Renal Plasma Flow (mL/g kid/min)	4.79 ± 0.33	2.13 ± 0.20^*
Renal Vascular Resistance (mmHg/mL/min/g kid)	1.93 ± 0.14	2.97 ± 0.32^*
Glomerular Filtration Rate (mL/g kid/min)	1.59 ± 0.18	0.61 ± 0.08^*
Filtration Fraction	0.356 ± 0.08	0.286 ± 0.04
B
Urine Volume (mL/kg/day)	31.8 ± 2.7	127.9 ± 16.9^*
Urine Na+ (mEq/kg/day)	4.00 ± 0.22	5.37 ± 0.26^*
Urine K+ (mEq/kg/day)	12.5 ± 0.52	16.3 ± 0.7^*
Urine Creatinine (mg/kg/day)	45.7 ± 1.6	32.0 ± 2.5^*
Creatinine Clearance (L/kg/day)	4.71 ± 0.75	2.63 ± 0.6^*
Urine Glucose (g/kg/day)	0.01 ± 0	6.08 ± 2.40^*
Urine Protein (mg/kg/day)	500 ± 20	2320 ± 90^*
U-Protein/Cr Clearance (mg/L)	119.8 ± 16.9	1182 ± 222^*
U-Protein/U-Creatinine Ratio	11.0 ± 0.01	74.0 ± 5.0^*

^* p < 0.05 two groups “t” test.

Table 6. Renal hystology in male, 29 weeks old, lean (+/fa) and obese (fa/fa^cp) ZDFxSHHF-hybrid rats ^* p < 0.05, Mann-Whitney test

	Lean 29 wks	Obese 29 wks
Kidney Weight (g)	1.61 ± 0.06	2.56 ± 0.06^*
Kidney/Body Weight (mg/g)	3.18 ± 0.07	4.18 ± 0.13^*
FSGS + FGGS (%)	0.1 ± 0.1	20.1 ± 3.2^*
Tubular Atrophy (0-3^+)	0	1.1 ± 0.1^*
Tubular Dilatation (0-4^+)	0.1 ± 0.1	2.7 ± 0.2^*
Cast (0-3^+)	0.1 ± 0.1	2.7 ± 0.2^*
Interst. Inflammation (0-3^+)	0	1.42 ± 0.2^*
Interstitial Fibrosis (0-3^+)	0	0.25 ± 0.2^*
Medial Hytpertrophy (0-3^+)	1.2 ± 0.2	1.75 ± 0.1^*
Arteriolar Sclerosis (0-3^+)	0.9 ± 0.2	1.3 ± 0.1

^* p < 0.05, Mann-Whitney test.