High-molecular weight hyaluronan reduced renal PKC activation in genetically diabetic mice.
The cluster determinant (CD44) seems to play a key role in tissues injured by diabetes type 2. CD44 stimulation activates the protein kinase C (PKC) family which in turn activates the transcriptional nuclear factor kappa B (NF-κB) responsible for the expression of the inflammation mediators such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), inducible nitric oxide synthase (iNOS), and matrix metalloproteinases (MMPs). Regulation of CD44 interaction with its ligands depends greatly upon PKC. We investigated the effect of the treatment with high-molecular weight hyaluronan (HA) on diabetic nephropathy in genetically diabetic mice. BKS.Cg-m+/+Lepr(db) mice had elevated plasma insulin from 15 days of age and high blood sugar levels at 4 weeks. The severe nephropathy that developed was characterized by a marked increased in CD44 receptors, protein kinase C betaI, betaII, and epsilon (PKC(βI), PKC(βII), and PKCε) mRNA expression and the related protein products in kidney tissue. High levels of mRNA and related protein levels were also detected in the damaged kidney for NF-κB, TNF-α, IL-6, IL-18, MMP-7, and iNOS. Chronic daily administration of high-molecular mass HA for 2 weeks significantly reduced CD44, PKC(βI), PKC(βII), and PKCα gene expression and the related protein production in kidney tissue and TNF-α, IL-6, IL-18, MMP-7, and iNOS expression and levels also decreased. Histological analysis confirmed the biochemical data. However, blood parameters of diabetes were unchanged. These results suggest that the CD44 and PKC play an important role in diabetes and interaction of high-molecular weight HA with these proteins may reduce inflammation and secondary pathologies due to this disease.
Campo
Giuseppe M
GM
Department of Biochemical, Physiological and Nutritional Sciences, Section of Medical Chemistry, School of Medicine, University of Messina, Policlinico Universitario, Messina, Italy. gcampo@unime.it
Avenoso
Angela
A
Micali
Antonio
A
Nastasi
Giancarlo
G
Squadrito
Francesco
F
Altavilla
Domenica
D
Bitto
Alessandra
A
Polito
Francesca
F
Rinaldi
Maria Grazia
MG
Calatroni
Alberto
A
D'Ascola
Angela
A
Campo
Salvatore
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020297:Mice, Congenic; D008970:Molecular Weight; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D064546:Protein Kinase C beta; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D020382:Interleukin-18; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D006820:Hyaluronic Acid; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051744:Protein Kinase C-epsilon; D020783:Matrix Metalloproteinase 7