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

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.

State of the Art in the Development of Human Serum Carnosinase Inhibitors

“…Notably, kidney function and inflammation correlate with serum and urinary excretion of serum carnosinase in humans [ 33 ]. The effect observed in humans reproduces the results of animal experiments, where reduced carnosinase activity and an increased concentration of peripheral carnosine produce kidney protection, especially in diabetic nephropathy [ 97 , 98 , 99 , 100 , 101 ]. On the contrary, the overexpression of serum carnosinase was reported to aggravate diabetes and renal impairment in transgenic mice [ 84 ].…”

Knock‐out of dipeptidase CN2 in human proximal tubular cells disrupts dipeptide and amino acid homeostasis and para‐ and transcellular solute transport

“…1,2 We now demonstrate that CN2 degrades carnosine only to a minor extent, in line with previous findings. 24 In contrast, both recombinant and proximal tubular cell CN2 have a broad specificity for degradation of a variety of DP, with high degradation rates. Depending on the DP, degradation rate was 4-to 300-fold higher than the degradation of carnosine by recombinant human CN1, 25 by CN1 in human proximal tubular epithelial cells and by human kidney tissue.…”