Publication

Human carnosinase 1 overexpression aggravates diabetes and renal impairment in BTBR(Ob/Ob)mice

Qiu, J., Albrecht, T., Zhang, S., Hauske, S. J., Rodriguez-Nino, A., Zhang, X., Nosan, D., Pastene, D. O., Sticht, C., Delatorre, C., van Goor, H., Porubsky, S., Kraemer, B. K. & Yard, B. A., 15-Aug-2020, In : Journal of Molecular Medicine. 98, 9, p. 1333-1346 14 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Jiedong Qiu
  • Thomas Albrecht
  • Shiqi Zhang
  • Sibylle J. Hauske
  • Angelica Rodriguez-Nino
  • Xinmiao Zhang
  • Darya Nosan
  • Diego O. Pastene
  • Carsten Sticht
  • Carolina Delatorre
  • Harry van Goor
  • Stefan Porubsky
  • Bernhard K. Kraemer
  • Benito A. Yard

Objective: To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). Methods: hCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice. Results: hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 μg/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator–activated receptor-alpha have been reported to play essential roles in DKD. Conclusions: Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. Key messages: Increased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD).BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype.Microarray revealed alterations by CN1 which are not altered by hyperglycemia.These genes have been described to play essential roles in DKD.Inhibiting CN1 could be beneficial in DKD.

Original languageEnglish
Pages (from-to)1333-1346
Number of pages14
JournalJournal of Molecular Medicine
Volume98
Issue number9
Publication statusE-pub ahead of print - 15-Aug-2020

    Keywords

  • Diabetic nephropathy, Carnosine, Antioxidants, Transgenic mice, Gene expression profiling, CNDP1 GENOTYPE, NEPHROPATHY, GENE, GLYCOSYLATION, METABOLISM, SECRETION, NOCTURNIN, PROTECTS, DISEASE

ID: 132901984