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Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes.

Martínez-García C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo TK, Chen S, Medina-Gomez G - PLoS ONE (2015)

Bottom Line: Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism.We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes.We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Genética Molecular. Universidad Rey Juan Carlos, Avda. de Atenas s/n, Alcorcón, Madrid, Spain.

ABSTRACT
In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome.

No MeSH data available.


Related in: MedlinePlus

PA produces motility alterations and decreased phosphorylation of p44/42 MAPK in podocytes.(A) Representative micrographs of scratch assays performed on podocytes treated with vehicle, 100, 500 or 750 μM of PA and quantification of the number of migrating cells after 24 h of treatment. Quantification was done based on the negative control. Results were normalized to cell viability data for each well as measured by a Crystal Violet method. Original magnification: 200×. (B) Representative immunoblot and quantification of phospho-p44/42 MAPK in protein extracts from different doses of PA-treated podocytes. Data is expressed as mean ± SEM and levels were normalized to total-ERK1/2 (phospho-p44/42-to-total-ERK1/2 ratio); *** p<0.001 PA vs. Veh.; ** p<0.01 PA vs. Veh.; * p<0.05 PA vs. Veh.
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pone.0142291.g006: PA produces motility alterations and decreased phosphorylation of p44/42 MAPK in podocytes.(A) Representative micrographs of scratch assays performed on podocytes treated with vehicle, 100, 500 or 750 μM of PA and quantification of the number of migrating cells after 24 h of treatment. Quantification was done based on the negative control. Results were normalized to cell viability data for each well as measured by a Crystal Violet method. Original magnification: 200×. (B) Representative immunoblot and quantification of phospho-p44/42 MAPK in protein extracts from different doses of PA-treated podocytes. Data is expressed as mean ± SEM and levels were normalized to total-ERK1/2 (phospho-p44/42-to-total-ERK1/2 ratio); *** p<0.001 PA vs. Veh.; ** p<0.01 PA vs. Veh.; * p<0.05 PA vs. Veh.

Mentions: Fig 6A showed changes in cell migration when podocytes were treated with different doses of PA. We found that podocyte motility was not significantly affected at the 100 or 500 μM dose of PA but was significantly changed at the 750 μM dose of PA. At 750 μM of PA we observed a significant decrease in the number of cells that migrated into the scratch compared to the cells treated with vehicle.


Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes.

Martínez-García C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo TK, Chen S, Medina-Gomez G - PLoS ONE (2015)

PA produces motility alterations and decreased phosphorylation of p44/42 MAPK in podocytes.(A) Representative micrographs of scratch assays performed on podocytes treated with vehicle, 100, 500 or 750 μM of PA and quantification of the number of migrating cells after 24 h of treatment. Quantification was done based on the negative control. Results were normalized to cell viability data for each well as measured by a Crystal Violet method. Original magnification: 200×. (B) Representative immunoblot and quantification of phospho-p44/42 MAPK in protein extracts from different doses of PA-treated podocytes. Data is expressed as mean ± SEM and levels were normalized to total-ERK1/2 (phospho-p44/42-to-total-ERK1/2 ratio); *** p<0.001 PA vs. Veh.; ** p<0.01 PA vs. Veh.; * p<0.05 PA vs. Veh.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4636358&req=5

pone.0142291.g006: PA produces motility alterations and decreased phosphorylation of p44/42 MAPK in podocytes.(A) Representative micrographs of scratch assays performed on podocytes treated with vehicle, 100, 500 or 750 μM of PA and quantification of the number of migrating cells after 24 h of treatment. Quantification was done based on the negative control. Results were normalized to cell viability data for each well as measured by a Crystal Violet method. Original magnification: 200×. (B) Representative immunoblot and quantification of phospho-p44/42 MAPK in protein extracts from different doses of PA-treated podocytes. Data is expressed as mean ± SEM and levels were normalized to total-ERK1/2 (phospho-p44/42-to-total-ERK1/2 ratio); *** p<0.001 PA vs. Veh.; ** p<0.01 PA vs. Veh.; * p<0.05 PA vs. Veh.
Mentions: Fig 6A showed changes in cell migration when podocytes were treated with different doses of PA. We found that podocyte motility was not significantly affected at the 100 or 500 μM dose of PA but was significantly changed at the 750 μM dose of PA. At 750 μM of PA we observed a significant decrease in the number of cells that migrated into the scratch compared to the cells treated with vehicle.

Bottom Line: Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism.We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes.We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Ciencias Básicas de la Salud, Área de Bioquímica y Genética Molecular. Universidad Rey Juan Carlos, Avda. de Atenas s/n, Alcorcón, Madrid, Spain.

ABSTRACT
In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome.

No MeSH data available.


Related in: MedlinePlus