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

Int J Mol Sci. 2020 Jul 10;21(14):4887. doi: 10.3390/ijms21144887.

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.

Keywords: CN1; Cndp1; anserine; carnosinase 1; carnosine; glucose homeostasis; kidney.

MeSH terms

  • Amino Acids / metabolism
  • Animals
  • Anserine / metabolism*
  • Blood Glucose / metabolism
  • Carnosine / metabolism*
  • Diabetic Nephropathies / metabolism
  • Dipeptidases / metabolism*
  • Female
  • Glucose / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Insulin / metabolism
  • Kidney
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / metabolism*

Substances

  • Amino Acids
  • Blood Glucose
  • HSP70 Heat-Shock Proteins
  • Insulin
  • RNA, Messenger
  • Carnosine
  • Dipeptidases
  • Anserine
  • Glucose