title: Carnosine treatment in combination with ACE inhibition in diabetic rats.
abstract: In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy. Male Sprague-Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4 weeks, rats were unilaterally nephrectomized and randomized for 24 weeks of treatment with carnosine, lisinopril or both. Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria. Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.
authors.affiliation: Centre for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany. Electronic address: Verena.Peters@med.uni-heidelberg.de.
authors.forename: V
authors.initials: V
authors.lastname: Peters
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Riedl
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Braunagel
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Höger
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Hauske
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Pfister
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Lanthaler
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Benck
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: H-P
authors.initials: HP
authors.lastname: Hammes
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: B K
authors.initials: BK
authors.lastname: Krämer
authors.affiliation: Centre for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany.
authors.forename: C P
authors.initials: CP
authors.lastname: Schmitt
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Yard
authors.affiliation: Vth Department of Medicine, Nephrology, Endocrinology, Diabetology & Rheumatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Köppel
mesh_terms: D000818:Animals; D002336:Carnosine / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin
chemical_list: D017127:Glycation End Products, Advanced; D013311:Streptozocin; D002336:Carnosine; D017706:Lisinopril
keywords: Carnosine; Cataract; Diabetes mellitus; Diabetic nephropathy; Proteinuria