A Global Cndp1-Knock-Out Selectively Increases Renal Carnosine and Anserine Concentrations in an Age- and Gender-Specific Manner in Mice

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.

Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats and humans

“…We also uncover that N-acetylcarnosine is the primary circulating HCD in human plasma and is continuously secreted from skeletal muscle into the circulation, which is further increased by physical exercise. An overview of the main findings is visualized in Previous endeavors to profile HCDs mostly focused on rodent tissues, and resulted in fragmented and sometimes contradictory literature (13,(22)(23)(24)(25). Our systematic approach and very sensitive state-ofthe-art UHPLC-MS/MS methodology facilitate direct comparison between tissues and species.…”

A Novel UPLC-MS/MS Method Identifies Organ-Specific Dipeptide Profiles

“…The role of amino acid transporters and their role in interorgan distribution of amino acids has been well described [ 8 ]. The tissue-specific distribution of carnosine and anserine with different carnosine-to-anserine ratios in the organs has been described in detail [ 13 , 14 ], but little is known about the distribution of other dipeptides and their relationship to amino acid metabolism. Moreover, it remains unknown to what extent organs can maintain dipeptides to release amino acids in adaption to the metabolic situation.…”

Extensive profiling of histidine‐containing dipeptides reveals species‐ and tissue‐specific distribution and metabolism in mice, rats, and humans

“…Previous endeavors to profile HCDs mostly focused on rodent tissues, and resulted in fragmented and sometimes contradictory literature. 13,[22][23][24][25] Our systematic approach and very sensitive state-of-the-art UHPLC-MS/MS methodology facilitate direct comparison between tissues and species. Our data contradicted some of the previous findings, for example, that human muscle contains only carnosine and no other HCDs, 2 that rat kidney, lung, plasma, and liver lack HCDs, 13 or that homocarnosine is exclusively found in the CNS, 26 with no presence of carnosine in the human brain or cerebrospinal fluid.…”