Abstract
Carnosinase 1 (CN1) is encoded by the Cndp1 gene and degrades carnosine and anserine, two natural histidine-containing dipeptides. In vitro and in vivo studies suggest carnosine- and anserine-mediated protection against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes mellitus. We have characterized the metabolic impact of CN1 in 11- and 55-week-old Cndp1-knockout (Cndp1-KO) mice and litter-matched wildtypes (WT). In Cndp1-KO mice, renal carnosine and anserine concentrations were gender-specifically increased 2- to 9-fold, respectively in the kidney and both most abundant in the renal cortex, but remained unchanged in all other organs and in serum. Renal oxidized/reduced glutathione concentrations, renal morphology and function were unaltered. In Cndp1-KO mice at week 11, renal asparagine, serine and glutamine levels and at week 55, renal arginine concentration were reduced. Renal heat-shock-protein 70 (Hspa1a/b) mRNA declined with age in WT but not in Cndp1-KO mice, transcription factor heat-shock-factor 1 was higher in 55-week-old KO mice. Fasting blood glucose concentrations decreased with age in WT mice, but were unchanged in Cndp1-KO mice. Blood glucose response to intraperitoneal insulin was gender- but not genotype-dependent, the response to intraperitoneal glucose injection was similar in all groups. A global Cndp1-KO selectively, age- and gender-specifically, increases renal carnosine and anserine concentrations, alters renal amino acid- and HSP70 profile and modifies systemic glucose homeostasis. Increase of the natural occurring carnosine and anserine levels in the kidney by modulation of CN1 represents a promising therapeutic approach to mitigate or prevent chronic kidney diseases such as diabetic nephropathy.
Highlights
Carnosinase 1 (CN1; EC 3.4.13.20) is a member of the M20 metalloprotease family with a catalytic domain featuring a dinuclear Zn2+ [1,2]
In 11-week-old Cndp1-KO mice renal carnosine and anserine concentrations were 4- and 2- fold higher compared to their age-matched WT controls and in 55-week-old KO mice 2- and 9-fold higher, respectively (Table 2, Figure 1)
Due to CN1 deficiency may be a non-disease; whereas accumulation of carnosine should protect against long-term sequelae of reactive metabolites accumulating, e.g., in diabetes and chronic renal failure [3,20] and may prevent cancer development [33]
Summary
Carnosinase 1 (CN1; EC 3.4.13.20) is a member of the M20 metalloprotease family with a catalytic domain featuring a dinuclear Zn2+ [1,2]. Anserine upregulates HSP70 expression under conditions of oxidative and glycating stress in tubular cells and in type 2 diabetic mice, anserine reduces blood glucose levels and vascular permeability and proteinuria [18]. In mammals and humans carnosine and anserine are the most abundant dipeptides, with highest concentrations in muscles [1]. Supplementation of carnosine in diabetic rodents consistently improved renal histology and function [20], vascular permeability [21], and wound healing [22], and glucose homeostasis [23,24,25,26]. Initial intervention studies in (pre-)diabetic patients yielded promising results, even though the half-life of carnosine in the human circulation is short even in subjects with low CN1 activity [27]
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