The role of carnosinase-1 and its mechanism in the progression of chronic kidney disease
Final Report Abstract
The studies performed in this grant proposal have combined epidemiologic studies, animal and in vitro models to obtain a better understanding of the role of carnosine/carnosinase in progression of renal disease. Indeed, cohort studies performed in Mannheim/Groningen and Hefei clearly suggest a deleterious effect of high carnosinase expression on the progression of CKD. Particularly, high carnosinase expression in urine is associated with renal function decline. Importantly in renal transplant recipients high expression of carnosinase in urine seems to be associated with graft failure. Also, in animal models high expression of carnosinase (CN1 TG-BTBRob/ob vs. WT BTBRob/ob and Neph-hAT1R TGR vs. WT rats) make these animals more vulnerable to develop renal pathology. High carnosinase expression is believed to be associated with low tissue carnosine concentrations, but this was not studied in the current project. Apart from degradation of carnosine, tissue carnosine levels are also depending on the expression of carnosine transporters, transports of ß-alanine which is synthesized to carnosine by the enzyme CARNS1. The carnsosine transporters (Pept1/2) as well as the ß-alanine transporter (TauT) were significantly higher in non-susceptible female as compared to susceptible male Neph-hAT1R TGR. The mechanism by which carnosine might beneficially affect renal pathology might rely on the effect of carnosine on glomerular hypertrophy. In all models tested in this project carnosine supplementation reduced glomerular hypertrophy. This might occur through modulation of the diameter of the afferent glomerular arterioles, albeit that the exact mechanism by which this is accomplished is still elusive. Nonetheless, studies performed in the Neph-hAT1R TGR model have suggested that carnosine supplementation influences the expression of renal RAAS components. In diabetic mice we hypothesize that the effect of carnosine might be related to tubuloglomerular feedback, either through the improvement of hyperglycemia or though the effect on proximal sodium reabsorption mediated via the proton-sodium exchanger-3 (NHE3). Our studies in CD73 KO mice are currently being analyzed may shed some light on this. Despite a reduction in glomerular hypertrophy, neither the mice nor rat studies clearly showed a beneficial effect on functional renal end-points. In keeping with previous studies in which reduction of albuminuria was shown our current results warrants further studies to underpin the protective effect of carnosine on the progression of CKD and dan diabetic kidney disease in particular. The in vivo experiments reported in reference 4 have suggested a new mechanism by which carnosine could alleviate high glucose induced tubular epithelial cell damage, inflammation and extracellular matrix accumulation through targeting of glycine N-methyltransferase (GNMT).
Publications
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Detection of carnosinase-1 in urine of healthy individuals and patients with type 2 diabetes: correlation with albuminuria and renal function. Amino Acids, 51(1), 17-25.
Rodriguez-Niño, Angelica; Gant, Christina M.; Braun, Jana D.; Li, Xia; Zhang, Shiqi; Albrecht, Thomas; Qiu, Jiedong; Bakker, Stephan J. L.; Laverman, Gozewijn D.; Krämer, Bernhard K.; Herold, Anna; Hauske, Sibylle J. & Yard, Benito A.
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Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy. Amino Acids, 51(4), 611-617.
Zhang, Shiqi; Albrecht, Thomas; Rodriguez-Niño, Angelica; Qiu, Jiedong; Schnuelle, Peter; Peters, Verena; Schmitt, Claus Peter; van den Born, Jacob; Bakker, Stephan J. L.; Lammert, Alexander; Krämer, Bernhard K.; Yard, Benito A. & Hauske, Sibylle J.
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Serum Carnosinase-1 and Albuminuria Rather than theCNDP1Genotype Correlate with Urinary Carnosinase-1 in Diabetic and Nondiabetic Patients with Chronic Kidney Disease. Journal of Diabetes Research, 2019 (2019, 12, 26), 1-12.
Rodriguez-Niño, Angelica; Hauske, Sibylle J.; Herold, Anna; Qiu, Jiedong; van den Born, Jacob; Bakker, Stephan J. L.; Krämer, Bernhard K. & Yard, Benito A.
