3
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Pentoxifylline for Renal Protection in Diabetic Kidney Disease. A Model of Old Drugs for New Horizons

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Diabetic kidney disease is one of the most relevant complications in diabetes mellitus patients, which constitutes the main cause of end-stage renal disease in the western world. Delaying the progression of this pathology requires new strategies that, in addition to the control of traditional risk factors (glycemia and blood pressure), specifically target the primary pathogenic mechanisms. Nowadays, inflammation is recognized as a critical novel pathogenic factor in the development and progression of renal injury in diabetes mellitus. Pentoxifylline is a nonspecific phosphodiesterase inhibitor with rheologic properties clinically used for more than 30 years in the treatment of peripheral vascular disease. In addition, this compound also exerts anti-inflammatory actions. In the context of diabetic kidney disease, pentoxifylline has shown significant antiproteinuric effects and a delay in the loss of estimated glomerular filtration rate, although at the present time there is no definitive evidence regarding renal outcomes. Moreover, recent studies have reported that this drug can be associated with a positive impact on new factors related to kidney health, such as Klotho. The use of pentoxifylline as renoprotective therapy for patients with diabetic kidney disease represents a new example of drug repositioning.

          Related collections

          Most cited references88

          • Record: found
          • Abstract: found
          • Article: not found

          The role of inflammatory cytokines in diabetic nephropathy.

          Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury.

            Macrophage-mediated renal injury has been implicated in progressive forms of glomerulonephritis; however, a role for macrophages in type 2 diabetic nephropathy, the major cause of end-stage renal failure, has not been established. Therefore, we examined whether macrophages may promote the progression of type 2 diabetic nephropathy in db/db mice. The incidence of renal injury was examined in db/db mice with varying blood sugar and lipid levels at 8 months of age. The association of renal injury with the accumulation of kidney macrophages was analyzed in normal db/+ and diabetic db/db mice at 2, 4, 6, and 8 months of age. In db/db mice, albuminuria and increased plasma creatinine correlated with elevated blood glucose and hemoglobin A1c (HbA1c) levels but not with obesity or hyperlipidemia. Progressive diabetic nephropathy in db/db mice was associated with increased kidney macrophages. Macrophage accumulation and macrophage activation in db/db mice correlated with hyperglycemia, HbA1c levels, albuminuria, elevated plasma creatinine, glomerular and tubular damage, renal fibrosis, and kidney expression of macrophage chemokines [monocyte chemoattractant protein-1 (MCP-1), osteopontin, migration inhibitory factor (MIF), monocyte-colony-stimulating factor (M-CSF)]. The accrual and activation of glomerular macrophages also correlated with increased glomerular IgG and C3 deposition, which was itself dependent on hyperglycemia. Kidney macrophage accumulation is associated with the progression of type 2 diabetic nephropathy in db/db mice. Macrophage accumulation and activation in diabetic db/db kidneys is associated with prolonged hyperglycemia, glomerular immune complex deposition, and increased kidney chemokine production, and raises the possibility of specific therapies for targeting macrophage-mediated injury in diabetic nephropathy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.

              Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.
                Bookmark

                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                27 February 2019
                March 2019
                : 8
                : 3
                : 287
                Affiliations
                [1 ]Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; jdonate@ 123456ull.edu.es (J.D.-C.); vtagua@ 123456funcanis.es (V.G.-T.); carlamferri@ 123456gmail.com (C.F.); emarnu87@ 123456gmail.com (E.M.-N.); carmenmora.fdez@ 123456gmail.com (C.M.-F.)
                [2 ]GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, 39008 Santander, Spain
                [3 ]Servicio de Medicina Interna, Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain; carolinahdezcarballo@ 123456gmail.com
                [4 ]Department of Dialyisis, AURA Nord, Saint Ouen, 93400 Paris, France; urena.pablo@ 123456wanadoo.fr
                [5 ]Department of Renal Physiology, Necker Hospital, University Paris Descartes, 75006 Paris, France
                [6 ]Laboratorio de Biología Celular en Enfermedades Renales, Universidad Autónoma Madrid, IIS-Fundación Jiménez Díaz, 28004 Madrid, Spain; marta.ruiz.ortega@ 123456uam.es
                [7 ]REDINREN (Red de Investigación Renal-RD16/0009/0007), Instituto de Salud Carlos III, 28029 Madrid, Spain
                [8 ]Departamento de Nefrología e Hipertensión, IIS-Fundación Jiménez Díaz y Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, Spain; aortiz@ 123456fjd.es
                [9 ]REDINREN (Red de Investigación Renal-RD16/0009/0001), Instituto de Salud Carlos III, 28029 Madrid, Spain
                [10 ]REDINREN (Red de Investigación Renal-RD16/0009/0022), Instituto de Salud Carlos III, 28029 Madrid, Spain
                [11 ]Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
                [12 ]Instituto de Tecnologías Biomédicas, Universidad de La Laguna, 38010 Santa Cruz de Tenerife, Spain
                Author notes
                [* ]Correspondence: jnavgon@ 123456gobiernodecanarias.org ; Tel.: +34-922-602389
                [†]

                These authors share senior authorship.

                Author information
                https://orcid.org/0000-0003-1494-6895
                https://orcid.org/0000-0002-2711-3836
                https://orcid.org/0000-0001-6757-1906
                https://orcid.org/0000-0002-9805-9523
                https://orcid.org/0000-0002-5015-7474
                Article
                jcm-08-00287
                10.3390/jcm8030287
                6463074
                30818852
                dfad8a3c-c1eb-4e79-9eaa-ecc7a2c0e2ce
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 January 2019
                : 22 February 2019
                Categories
                Review

                pentoxifylline,diabetic kidney disease,inflammation,klotho

                Comments

                Comment on this article