Morphometric detection of incipient glomerular lesions in diabetic nephropathy in rats. Protective effects of ACE inhibition.
BACKGROUND
Glomerulosclerosis is the main renal lesion complicating diabetes in humans and in experimental models. Angiotensin I-converting enzyme (ACE) inhibitors are effective in preventing the development of diabetic nephropathy. Incipient glomerular lesions were explored in streptozotocin-diabetic rats at a stage when glomerulosclerosis was not yet established. The modulation of such early glomerular lesions by a new ACE inhibitor (Trandolapril (T) at high or low doses was assessed.


METHODS
Five groups of rats were designed as follows: (a) nondiabetic control rats, (b) diabetic rats, (c) diabetic rats treated with 0.1 mg/kg/day of T, (d) diabetic rats treated with 1 mg/kg/day of T, and (e) nondiabetic rats treated with 1 mg/kg/day of T. The rats were killed at 1, 3, and 6 months after the beginning of the treatment. The kidneys were studied using a powerful morphometric technique at optical microscopic level with an image analyzer to measure the following glomerular parameters to assess the development of incipient glomerular lesions: (a) total glomerular surface area, (b) glomerular tuft surface area, (c) mesangial surface area, (d) ratio of the mesangial surface area to the glomerular tuft surface area, and (e) mean thickness of the Bowman's capsule. In parallel, albuminuria was measured.


RESULTS
The results showed the development of glomerular hypertrophy in parallel with the increase in glomerular mesangial domain and in albuminuria with diabetes. They also demonstrated that ACE inhibitor given at a high dose is significantly effective in reducing glomerular hypertrophy and the expansion of the mesangial domain. ACE inhibitor given at a low dose tended to reduce glomerular hypertrophy and the expansion of the mesangial domain. Furthermore, ACE inhibitor at both doses completely abolished the albuminuria increase, maintaining the levels of albuminuria within the range of young nondiabetic rats.


CONCLUSIONS
Using morphometric image analysis, incipient glomerular changes can be detected before glomerulosclerosis is patent in experimental diabetes. Moreover, they can be easily and reliably quantified by this technique, allowing comparison among experimental groups. These changes can be prevented by ACE inhibition.
Sassy-Prigent
C
C
INSERM U 430, Hôpital Broussais, Paris, France.
Heudes
D
D
Jouquey
S
S
Auberval
D
D
Belair
M F
MF
Michel
O
O
Hamon
G
G
Bariety
J
J
Bruneval
P
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
D000806:Angiotensin-Converting Enzyme Inhibitors; D013311:Streptozocin