Carnosine Prevents Apoptosis of Glomerular Cells and Podocyte Loss in STZ Diabetic Rats

Riedl, Eva; Pfister, Frederick; Braunagel, Margarita; Brinkkoetter, Paul T.; Sternik, Paula; Deinzer, Martina; Bakker, Stephan J. L.; Henning, Robert H.; Born, Jacob van den; Kraemer, Bernhard; Navis, Gerjan; Hammes, Hans‐Peter; Yard, Benito A.; Koeppel, Hannes

doi:10.1159/000331740

Cited by 106 publications

(87 citation statements)

References 52 publications

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“…Our study is the first Podocytes are inter-connected by slit diaphragms (SDs) that covered the exterior basement membrane surface of the glomerular capillary and maintain the structural integrity of glomerular capillary loops. Recently, several studies have demonstrated that podocyte apoptosis plays a key role in the pathogenesis of DN [19][20][21][22] . Thus, preventing or inhibiting podocyte apoptosis may provide an obvious therapeutic modality for DN treatment.…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS.

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Section: Discussionmentioning

confidence: 99%

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

et al. 2016

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“…We therefore provide a new mechanism by which carnosine improves the metabolic control in diabetes and protect against the development of complications in diabetes. Even though carnosine shown protective effect in several animal models for complications of diabetes (Pfister et al 2011, Riedl et al 2011, Ansurudeen et al 2012, Yapislar & Aydogan 2012, Brown et al 2014, Peters et al 2014, Menini et al 2015 and strongly suggested to be relevant for diabetes complications in humans (Ahluwalia et al 2011, Kurashige et al 2013) the exact mechanism of action is still unraveled. Here we suggest a potential mechanism by showing that carnosine complexly modulates IGFBP1 by different mechanisms, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Carnosine supplementation mitigates DN, reduces renal vasculopathy, and normalizes vascular permeability in diabetic mice. In streptozotocin-induced, diabetic rats, carnosine treatment prevents apoptosis of glomerular cells and podocyte loss and vascular damage (Riedl et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

Forsberg¹,

Botusan²,

Wang³

et al. 2015

Journal of Endocrinology

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IGF binding protein 1 (IGFBP1) is a member of the binding proteins for the IGF with an important role in glucose homeostasis. Circulating IGFBP1 is derived essentially from the liver where it is mainly regulated negatively by insulin. Carnosine, a natural antioxidant, has been shown to improve metabolic control in different animal models of diabetes but its mechanisms of action are still not completely unraveled. We therefore investigate the effect of carnosine treatment on the IGFBP1 regulation in db/db mice. Db/db mice and heterozygous non-diabetic mice received for 4 weeks regular water or water supplemented with carnosine. Igfbp1 mRNA expression in the liver was evaluated using qPCR and the protein levels in plasma by western blot. Plasma IGF1 and insulin were analyzed using immunoassays. HepG2 cells were used to study the in vitro effect of carnosine on IGFBP1. The modulation of hypoxia inducible factor-1 alpha (HIF-1a) which is the central mediator of hypoxia-induction of IGFBP1 was analyzed using: WB, reporter gene assay and qPCR. Carnosine decreased the circulating IGFBP1 levels and the liver expression Igfbp1, through a complex mechanism acting both directly by suppressing the HIF-1a-mediated IGFBP1 induction and indirectly through increasing circulating insulin level followed by a decrease in the blood glucose levels and increased the plasma levels or IGF1. Reduction of IGFBP1 in diabetes through insulin-dependent and insulin-independent pathways is a novel mechanism by which carnosine contributes to the improvement of the metabolic control in diabetes.

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“…Both human genetic association studies and animal models suggest a pivotal role for the carnosinecarnosinase system in microvascular complications of diabetes (3,19,33,34,40).…”

mentioning

confidence: 99%

“…Although formal proof for this assumption is still lacking in humans, studies in type 1 and 2 diabetic rodent models revealed that carnosine supplementation caused a later onset of hyperglycemia and a milder course of diabetes with significantly less renal damage (30,31,33,34,36). This beneficial effect can be explained in part by carnosine's physiological and biochemical properties (9).…”

mentioning

confidence: 99%

Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes

Stegen

Sigal

Kenny

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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A particular allele of the carnosinase gene (CNDP1) is associated with reduced plasma carnosinase activity and reduced risk for nephropathy in diabetic patients. On the one hand, animal and human data suggest that hyperglycemia increases plasma carnosinase activity. On the other hand, we recently reported lower carnosinase activity levels in elite athletes involved in high-intensity exercise compared with untrained controls. Therefore, this study investigates whether exercise training and the consequent reduction in hyperglycemia can suppress carnosinase activity and content in adults with type 2 diabetes. Plasma samples were taken from 243 males and females with type 2 diabetes (mean age = 54.3 yr, SD = 7.1) without major microvascular complications before and after a 6-mo exercise training program [4 groups: sedentary control ( n = 61), aerobic exercise ( n = 59), resistance exercise ( n = 63), and combined exercise training ( n = 60)]. Plasma carnosinase content and activity, hemoglobin (Hb) A1c, lipid profile, and blood pressure were measured. A 6-mo exercise training intervention, irrespective of training modality, did not decrease plasma carnosinase content or activity in type 2 diabetic patients. Plasma carnosinase content and activity showed a high interindividual but very low intraindividual variability over the 6-mo period. Age and sex, but not Hb A1c, were significantly related to the activity or content of this enzyme. It can be concluded that the beneficial effects of exercise training on the incidence of diabetic complications are probably not related to a lowering effect on plasma carnosinase content or activity.

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Carnosine Prevents Apoptosis of Glomerular Cells and Podocyte Loss in STZ Diabetic Rats

Cited by 106 publications

References 52 publications

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

Carnosine decreases IGFBP1 production in db/db mice through suppression of HIF-1

Aerobic and resistance training do not influence plasma carnosinase content or activity in type 2 diabetes

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