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+/+Leprdb 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 (PKCβI, PKCβII, 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, PKCβI, PKCβII, 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.

Research highlights►This study could be an additional step for a better understanding of the complex mechanism that underlies diabetes. Of particular interest is the possibility to obtain useful data for the future development of new molecules that are active in the prevention and the treatment of diabetes. ►The research in this field has made significant progress in the last years. Many studies have redefined the molecular basis of diabetes. The conventional view, although fundamental, has been supplanted by a new vision, one clearly supported by experimental and clinical data, of the diabetes disease, especially for type 2 diabetes which is age-related. In fact, it is now clear that inflammation is a key process in the onset of diabetes and that the inflammatory milieu in this detrimental disease significantly contributes to the development of many of the complications of diabetes, including diabetic nephropathy. The links between this inflammatory state and the development and progression of diabetic nephropathy involve a highly complex network of processes. Diverse inflammatory molecules play significant roles in this scenario, including CD44, PKC isoforms, chemoattractant cytokines, proinflammatory cytokines, ROS and MMPs. Consequently, on the basis of this new knowledge, a totally new approach can be planned to modulate the inflammatory mechanism that seems to underlie diabetic disease. It is widely recognised that, diabetic nephropathy is one of the worst consequences of this disease. At present, the current treatments available for diabetes complications are still suboptimal, both in terms of preventing their appearance and in halting their progression. A better understanding of the role of inflammatory molecules and processes in the context of diabetes complications will facilitate the development of new and improved therapeutic targets and strategies that can be translated successfully into clinical applications. ►It is under this new vision of the molecular basis of diabetic complications that we have performed our research study, aiming to clarify some important aspects of this disease and its damaging consequences that are currently not investigated or not well clarified. The obtained results confirmed the central role played by the CD44 receptor and the activation of PKC isoforms as well as the damage exerted by proinflammatory cytokines and the other inflammation mediators. The protective role exerted by high-molecular weight hyaluronan could be useful for future pharmacological strategies development in the treatment of diabetic complication.