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Open AccessArticle

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

1
Centre for Paediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany
2
Nonclinical Drug Safety Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
3
Drug Metabolism & Pharmacokinetics Germany, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany
4
Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, 69120 Heidelberg, Germany
5
Tissue Bank of the National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
6
Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany
7
Institute of Pharmacology, University of Heidelberg, 69120 Heidelberg, Germany
8
Department of Cardiovascular Physiology, University of Heidelberg, 69120 Heidelberg, Germany
9
Center for Model System and Comparative Pathology (CMCP), Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
10
Centre for Organismal Studies (COS), University of Heidelberg, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Both authors contributed equally.
Int. J. Mol. Sci. 2020, 21(14), 4887; https://doi.org/10.3390/ijms21144887
Received: 4 May 2020 / Revised: 3 July 2020 / Accepted: 6 July 2020 / Published: 10 July 2020
(This article belongs to the Special Issue Biological Properties of Secondary Metabolites and Natural Compounds)
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. View Full-Text
Keywords: carnosinase 1; CN1; Cndp1; carnosine; anserine; kidney; glucose homeostasis carnosinase 1; CN1; Cndp1; carnosine; anserine; kidney; glucose homeostasis
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Weigand, T.; Colbatzky, F.; Pfeffer, T.; Garbade, S.F.; Klingbeil, K.; Colbatzky, F.; Becker, M.; Zemva, J.; Bulkescher, R.; Schürfeld, R.; Thiel, C.; Volk, N.; Reuss, D.; Hoffmann, G.F.; Freichel, M.; Hecker, M.; Poth, T.; Fleming, T.; Poschet, G.; Schmitt, C.P.; Peters, V. 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, 21, 4887.

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