Human CN1 overexpression aggravates diabetes and renal impairment in BTBR ob/ob mice

Introduction:

The CNDP1 (CTG)5 genotype is associated with low serum carnosinase 1 (CN1) concentrations and protects against diabetic kidney disease (DKD) in patients with type 2 diabetes. Yet, no formal proof exists that high serum CN1 concentrations affect the progression of DN. We generated human CN1 (hCN1) transgenic BTBR ob/ob mice to assess if the presence of serum CN1 influences renal impairment and if this is accompanied by large changes in the renal transcriptome.

Methods:

We therefore generated human CN1 transgenic (TG) mice in the BTBR ob/ob background, over-expressing human CN1 in serum. CN1, carnosine were assessed in serum and kidney. Clinical parameters were assessed after 18 weeks observation.

Results:

Serum and renal carnosine concentrations were lower in hCN1 transgenic mice. Diabetic hCN1 BTBR ob/ob mice displayed higher levels of FPG, HbA1c, glycosuria, proteinuria and albumin-creatinine ratios (ACR) accompanied by an increased mean glomerular -and glomerular tuft area and a slightly increased mortality at week 24. Gene-expression profiling of renal tissue disclosed hierarchical clustering between wt/ob, ob/ob and hCN1 ob/ob mice. While differences in gene expression between diabetic and non-diabetic mice ranged from 7.4 fold upregulation (3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (HMGCS2)) to 32 fold downregulation (histidine decarboxylase (hdc)), differences between diabetic hCN1 ob/ob and ob/ob mice were significantly less.

Conclusion:

In conclusion, a high serum carnosinase activity aggravates hyperglycemia and renal impairment in type 2 diabetic mice. The benefit of carnosine supplementation is completely lost in these mice. Therapeutic inhibition of carnosinase with or without carnosine supplementation is currently studied.