title: Hyperosmolarity induced by high glucose promotes senescence in human glomerular mesangial cells.
abstract: Hyperglycemia is involved in the diabetic complication of different organs and can elevate serum osmolarity. Here, we tested whether hyperosmolarity promoted by high glucose levels induces cellular senescence in renal cells. We treated Wistar rats with streptozotocin to induce diabetes or with consecutive daily injections of mannitol to increase serum osmolarity and analyzed p53 and p16 genes in renal cortex by immunohistochemistry. Both diabetic and mannitol treated rats showed a significant increase in serum osmolarity, without significant signs of renal dysfunction, but associated with increased staining for p53 and p16 in the renal cortex. An increase in p53 and p16 expression was also found in renal cortex slices and glomeruli isolated from healthy rats, which were later treated with 30 mM glucose or mannitol. Intracellular mechanisms involved were analyzed in cultured human glomerular mesangial cells treated with 30 mM glucose or mannitol. After treatments, cells showed increased p53, p21 and p16 expression and elevated senescence-associated β-galactosidase activity. Senescence was prevented when myo-inositol was added before treatment. High glucose or mannitol induced constitutive activation of Ras and ERK pathways which, in turn, were activated by oxidative stress. In summary, hyperosmolarity induced renal senescence, particularly in glomerular mesangial cells, increasing oxidative stress, which constitutively activated Ras-ERK 1/2 pathway. Cellular senescence could contribute to the organ dysfunction associated with diabetes.
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: del Nogal
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Troyano
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodriguez-Puyol
authors.affiliation: Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; Nephrology Section, Principe de Asturias University Hospital, Alcalá de Henares, Spain; FIBROTEAM, Comunidad de Madrid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Rodriguez-Puyol
authors.affiliation: Department of System Biology, University of Alcalá, Alcalá de Henares, Madrid, Spain; Reina Sofia Institute of Nephrology research (IRSIN), Spain; REDinREN from ISCIII, Madrid, Spain; FIBROTEAM, Comunidad de Madrid, Spain. Electronic address: mpiedad.ruiz@uah.es.
authors.forename: María P
authors.initials: MP
authors.lastname: Ruiz-Torres
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D009997:Osmotic Pressure; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D018631:ras Proteins
chemical_list: D018631:ras Proteins; D005947:Glucose
keywords: Cellular senescence; Hyperglycemia; Hyperosmolarity; Oxidative stress; Ras