Advanced glycosylation end-products in experimental murine diabetic nephropathy: effect of islet isografting and of aminoguanidine.
The effects of islet isografting and of aminoguanidine on the accumulation of advanced glycosylation end-products (AGE) in renal basement membranes were studied in Streptozotocin (STZ)-induced diabetes mellitus in female BALB/c mice. The characteristic autofluorescence of glycosylated collagen was used to quantitate AGE. We studied the effect of islet isografting using 3 groups of mice, sacrificed at age 13 to 15 months: group A, untreated diabetes (STZ 250 mg/kg intravenously at age 6 to 8 weeks); group B, untreated diabetes for 7 months, then successfully grafted with cultured islet cells; and group C, age-matched normal control animals. At sacrifice, AGE were measured in digests of renal basement membranes as collagen-linked fluorescence/unit of hydroxyproline. Group A animals had significantly greater renal basement membrane glycosylation than did the other 2 groups, (group A median 88.0 arbitrary units/mumol hydroxyproline, range 30.2 to 127.5; group B median 19.4, range 5.1 to 56.8; group C median 2.9 range 0-13.5; p = .001 A versus B). To study the effect of aminoguanidine, 4 groups of animals were used: group 1, untreated diabetics (STZ 250 mg/kg intravenously at age 6 to 8 weeks); group 2, diabetics treated with aminoguanidine 50 mg/kg intraperitoneally daily; group 3, age-matched control animals, and group 4, age-matched controls treated with aminoguanidine. At sacrifice after 7 months, AGE were measured in digests of renal basement membranes as collagen-linked fluorescence/unit of hydroxyproline. Aminoguanidine significantly attenuated the accumulation of AGE in diabetic mice (group 1 median 47.2 arbitrary units/mumol hydroxyproline, range 16.1 to 56.0; group 2 median 24.4, range 5.0 to 37.7; group 3 median 13.6, range 0 to 30.3; group 4 median 10.8, range 2.1 to 17.2; p less than 0.01, groups 1 versus 2). These results indicate that further basement membrane glycosylation is prevented by restoration of euglycemia by islet grafting after a significant duration of diabetes, and that aminoguanidine prevents AGE accumulation despite hyperglycemia.
Nicholls
K
K
Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia.
Mandel
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D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D011506:Proteins / Q000378:metabolism; D014185:Transplantation, Isogeneic
D006146:Guanidines; D011506:Proteins; C004479:pimagedine