Renoprotective effects of a novel inhibitor of advanced glycation.
OBJECTIVE
ALT-946, an inhibitor of advanced glycation with a minimal inhibitory effect on nitric oxide synthase, was compared with aminoguanidine in experimental diabetic nephropathy.


METHODS
In vitro and in vivo assays were used to assess the ability of ALT-946 to inhibit AGE-protein cross-link formation. Diabetic animals were randomly allocated into groups receiving aminoguanidine for 32 weeks, ALT-946 or vehicle (untreated). As a delayed intervention protocol, an additional diabetic group was treated with ALT-946 from week 16 to week 32 of the study. Non-diabetic rats were studied concurrently. Systolic blood pressure, body weight, plasma glucose, glycated haemoglobin and urinary albumin excretion were measured serially. Accumulation of advanced-glycation end products in the kidney was assessed by immunohistochemistry.


RESULTS
The ALT-946 inhibitor was more potent than aminoguanidine in inhibiting AGE-protein cross-linking both in vitro and in vivo. Increased albuminuria observed in diabetic rats was attenuated in all three treatment groups. We found no difference in body weight, blood pressure or glycaemic control with any of the treatments. The untreated diabetic group had a twofold increase in glomerular staining for advanced-glycation end products compared with the diabetic groups which received treatment.


CONCLUSIONS
ALT-946 is a potent inhibitor of advanced renal glycation end-product accumulation and reproduces the renoprotective effects of aminoguanidine. Therefore, ALT-946 should be considered as a treatment for preventing or retarding diabetic nephropathy.
Forbes
J M
JM
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, West Heidelberg, Australia.
Soulis
T
T
Thallas
V
V
Panagiotopoulos
S
S
Long
D M
DM
Vasan
S
S
Wagle
D
D
Jerums
G
G
Cooper
M E
ME
D000818:Animals; D003432:Cross-Linking Reagents; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D004791:Enzyme Inhibitors; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000037:antagonists & inhibitors*; D006146:Guanidines / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000737:chemistry; D007678:Kidney Glomerulus / Q000737:chemistry; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine
D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D012710:Serum Albumin, Bovine; D019001:Nitric Oxide Synthase; C004479:pimagedine