Influence of carnosine and carnosinase-1 on diabetes-induced afferent arteriole vasodilation: implications for glomerular hemodynamics

Abstract

Background: Dysregulation in glomerular hemodynamics favors hyperfiltration in diabetic kidney disease (DKD). Although carnosine supplementation ameliorates features of DKD, its effect on glomerular vasoregulation is not known. We assessed the influence of carnosine and carnosinase-1 (CN1) on afferent glomerular arteriole vasodilation and its association with glomerular size, hypertrophy and nephrin expression in diabetic BTBRob/ob mice. Methods: Two cohorts of mice including appropriate controls were studied i.e., diabetic mice receiving oral carnosine supplementation (cohort 1) and human CN1 (hCN1) transgenic (TG) diabetic mice (cohort 2). Lumen area ratio (LAR) of the afferent arterioles and glomerular parameters were measured by conventional histology. Three-dimensional analysis using a tissue clearing strategy was also employed.Results: In both cohorts, LAR was significantly larger in diabetic BTBRob/ob vs non-diabetic BTBRwt/ob mice (0.41±0.05 vs 0.26±0.07; p<0.0001) and (0.42±0.06 vs 0.29±0.04; p<0.0001), and associated with glomerular size (cohort 1: r =0.55, p=0.001; cohort 2: r=0.89, p<0.0001). LAR was partially normalized by oral carnosine supplementation (0.34±0.05 vs 0.41±0.05; p=0.004), but did not differ between hCN1 TG and wild type (WT) BTBRob/ob mice. In hCN1 TG mice, serum CN1 concentrations correlated with LAR (r=0.90; p=0.006). Diabetic mice displayed decreased nephrin expression and increased glomerular hypertrophy. This was not significantly different in hCN! TG BTBRob/ob mice (p=0,06 and p=0,08, respectively).Conclusion: Carnosine and CN1 may affect intra-glomerular pressure in an opposing manner through regulation of afferent arteriolar tone. This study corroborates previous findings on the role of carnosine in the progression of DKD.

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 ].…”

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

“…Anserine exerts higher antioxidative action than carnosine and activates the intracellular Hsp70/HO-1 defense system under oxidative and glycative stress [ 11 ]. Carnosine supplementation preserved diabetic kidney morphology, i.e., glomerular hypertrophy [ 12 ] and podocyte number [ 13 , 14 ], inhibited mesangial expansion [ 15 ] and affected intraglomerular pressure [ 16 ]. In several but not all of these studies, however, glucose homeostasis was also improved with carnosine supplementation [ 17 , 18 , 19 , 20 ].…”

Carnosine Did Not Affect Vascular and Metabolic Outcomes in Patients with Prediabetes and Type 2 Diabetes: A 14-Week Randomized Controlled Trial

“…Likewise, carnosine administration reduced serum creatinine and urea levels in diabetic rats [64]. Carnosine was also effective in reducing glomerular hypertrophy [65] and podocyte apoptosis and loss [66]. In subjects with diabetic nephropathy, carnosine supplementation could decrease urinary TGF-β levels to serve as a marker of renal injury [24].…”