Abstract
Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. High-glucose stress initiated stress response by increasing intracellular heat shock protein 70 (Hsp70), sirtuin-1 (Sirt-1), thioredoxin (Trx), glutamate-cysteine ligase (gamma-glutamyl cysteine synthetase; γ-GCS) and heme oxygenase-1 (HO-1) in podocytes by 30–50% compared to untreated cells. Carnosine (1 mM) also induced a corresponding upregulation of these intracellular stress markers, which was even more prominent compared to glucose for Hsp70 (21%), γ-GCS and HO-1 (13% and 20%, respectively; all p < 0.001). Co-incubation of carnosine (1 mM) and glucose (25 mM) induced further upregulation of Hsp70 (84%), Sirt-1 (52%), Trx (35%), γ-GCS (90%) and HO-1 (73%) concentrations compared to untreated cells (all p < 0.001). The glucose-induced increase in 4-hydroxy-trans-2-nonenal (HNE) and protein carbonylation was reduced dose-dependently by carnosine by more than 50% (p < 0.001). Although podocytes tolerated high carnosine concentrations (10 mM), high carnosine levels only slightly increased Trx and γ-GCS (10% and 19%, respectively, compared to controls; p < 0.001), but not Hsp70, Sirt-1 and HO-1 proteins (p not significant), and did not modify the glucose-induced oxidative stress response. In podocytes, carnosine induced cellular stress tolerance and resilience pathways and was highly effective in reducing high-glucose-induced glycative and lipoperoxidative stress. Carnosine in moderate concentrations exerted a direct podocyte molecular protective action.
Highlights
Carnosine (β-alanyl-L-histidine) and anserine (β-alanyl-N-methyl-L-histidine) are natural histidine-containing dipeptides (HDPs), commonly found in animal tissues that are excitable, but are absent in fungi, plants or other eukaryotes [1]
To investigate the effect of carnosine antioxidant capacity to modulate the vitagene pathway, we performed experiments in which the levels of the inducible isoform heat shock protein 70 (Hsp70) were evaluated by western blot analysis in SV-40 immortalized murine podocytes in the presence of both high glucose
Glucose-stressed podocytes increased Hsp70 protein concentration by 30–50% compared to untreated cells (Figure 1, Table 1; p < 0.001) and normalized to respective β-actin concentrations
Summary
Carnosine (β-alanyl-L-histidine) and anserine (β-alanyl-N-methyl-L-histidine) are natural histidine-containing dipeptides (HDPs), commonly found in animal tissues that are excitable, but are absent in fungi, plants or other eukaryotes [1]. Several in vivo studies demonstrated the potential of carnosine as an agent for the attenuation of different types of chronic diseases related to oxidative and glycative stress [3,4], such as diabetes-associated complications, in particular, diabetic nephropathy (DN) [5,6]. Carnosine has a role in the scavenging of carbonyls [5,6,7,8,9] and reactive oxygen species [10], and inhibits glycation [11] and angiotensin-converting enzymes [12,13]. Oxidative and glycative stress represents the starting point for the induction of markers of reactive oxygen species (ROS), advanced glycation end products (AGEs), protein carbonylation and lipid peroxidation adducts (HNE adducts) that are crucial to the initiation of apoptosis in podocytes [17]. It has been discussed that carnosine may prevent apoptosis [19,20]
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