Carnosinase-1 Knock-Out Reduces Kidney Fibrosis in Type-1 Diabetic Mice on High Fat Diet

Author:

Pfeffer Tilman12ORCID,Wetzel Charlotte1,Kirschner Philip1,Bartosova Maria1ORCID,Poth Tanja34ORCID,Schwab Constantin4,Poschet Gernot5ORCID,Zemva Johanna6,Bulkescher Ruben6,Damgov Ivan7,Thiel Christian1,Garbade Sven F.1ORCID,Klingbeil Kristina1,Peters Verena1ORCID,Schmitt Claus Peter1ORCID

Affiliation:

1. Centre for Paediatric and Adolescent Medicine, University of Heidelberg, 69120 Heidelberg, Germany

2. Tissue Bank of the German Center for Infection Research (DZIF), Partner Site Heidelberg, Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany

3. Center for Model System and Comparative Pathology (CMCP), Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany

4. Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany

5. Centre for Organismal Studies (COS), Metabolomics Core Technology Platform, University of Heidelberg, 69120 Heidelberg, Germany

6. Internal Medicine I and Clinical Chemistry, University Hospital Heidelberg, 69120 Heidelberg, Germany

7. Institute of Medical Biometry and Informatics, University of Heidelberg, 69120 Heidelberg, Germany

Abstract

Carnosine and anserine supplementation markedLy reduce diabetic nephropathy in rodents. The mode of nephroprotective action of both dipeptides in diabetes, via local protection or improved systemic glucose homeostasis, is uncertain. Global carnosinase-1 knockout mice (Cndp1-KO) and wild-type littermates (WT) on a normal diet (ND) and high fat diet (HFD) (n = 10/group), with streptozocin (STZ)-induced type-1 diabetes (n = 21–23/group), were studied for 32 weeks. Independent of diet, Cndp1-KO mice had 2- to 10-fold higher kidney anserine and carnosine concentrations than WT mice, but otherwise a similar kidney metabolome; heart, liver, muscle and serum anserine and carnosine concentrations were not different. Diabetic Cndp1-KO mice did not differ from diabetic WT mice in energy intake, body weight gain, blood glucose, HbA1c, insulin and glucose tolerance with both diets, whereas the diabetes-related increase in kidney advanced glycation end-product and 4-hydroxynonenal concentrations was prevented in the KO mice. Tubular protein accumulation was lower in diabetic ND and HFD Cndp1-KO mice, interstitial inflammation and fibrosis were lower in diabetic HFD Cndp1-KO mice compared to diabetic WT mice. Fatalities occurred later in diabetic ND Cndp1-KO mice versus WT littermates. Independent of systemic glucose homeostasis, increased kidney anserine and carnosine concentrations reduce local glycation and oxidative stress in type-1 diabetic mice, and mitigate interstitial nephropathy in type-1 diabetic mice on HFD.

Funder

Deutsche Forschungsgemeinschaft

Olympia Morata Program

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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