Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress

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.

Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage

“…Another limitation may be the lack of specificity of Car and Res in protecting from glucose-induced changes of HIF-1α activity, as these compounds have other pleiotropic effects beyond their MGO-sequestering and GLO-1 inducer activities. In fact, both Car and Res have been shown to exert indirect antioxidant effects to upregulate endogenous antioxidants and other cell stress response genes [ 78 , 79 , 80 , 81 ]. However, the efficacy of Car to prevent HIF-α changes induced by MGO, including the reduced prolyl hydroxylation by PHD2, can only be attributed to its carbonyl trapping activity, thus supporting the concept that the protective effects exerted by both compounds in HG conditions were mediated by their ability to prevent glycolysis-induced MGO accumulation.…”

Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice

“…Podocytes play a major role in preserving the integrity of glomerular function under normal conditions. 34 Structural and functional impairment of podocytes, which constitute the outer layer of the renal glomerular filtration barrier, will lead to proteinuria and in patients with diabetes mellitus, thus, play a pivotal role in the development of diabetic nephropathy. 35 Nephrin is an essential component of the slit diaphragms, which is necessary to maintain selective glomerular filtration.…”

Moringa oleifera Protects SH-SY5YCells from DEHP-Induced Endoplasmic Reticulum Stress and Apoptosis

“…The latter involves redox-sensitive genes, such as heme oxygenase-1 (HO-1), heat shock proteins (Hsps), thioredoxin, and the sirtuinsystem, termed vitagenes [ 32 , 33 , 34 ]. Notably, recent evidence suggested that polyphenols from plant and fungal species activate the Nrf2/HO-1 pathway, conferring cytoprotection against ROS generation in a hormetic-like manner [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. HO-1 catalyzes the conversion of heme to biliverdin, ferrous iron, and carbon monoxide, which can directly scavenge free radicals.…”