New paradigms in cell death in human diabetic nephropathy

Department of Nefrologia, IIS Fundacion Jimenez Diaz, Madrid, Spain.
Kidney International (Impact Factor: 8.56). 10/2010; 78(8):737-44. DOI: 10.1038/ki.2010.270
Source: PubMed


Cell death is thought to contribute to progressive renal cell depletion in diabetic nephropathy. Unbiased gene expression profiling identified novel cell death molecules in human diabetic nephropathy. The expression of TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin, and receptors Fas (a Fas ligand receptor) and CD74 (a migration inhibitory factor (MIF) receptor) were induced in human diabetic nephropathy. Cell culture studies supported the functional relevance of this observation and the relationship to a high glucose environment. To define novel proapoptotic proteins upregulated in diabetic nephropathy, functional genomic screens for novel apoptosis mediators were integrated with genome-wide expression profiling and identified candidates for further functional analysis, including brain acid-soluble protein 1 (BASP1). Several lines of evidence point toward induction of endoplasmic reticulum stress response in human diabetic nephropathy. Functional studies defining an unequivocal contribution of endoplasmic reticulum stress to cell death in this setting are still needed. Further comparative studies will be required to define whether there is a specific aspect of apoptosis in progressive human diabetic nephropathy or whether the mechanisms are shared among all patients with chronic kidney disease. The next challenge will be to define the consequence of therapeutic interference of the apoptosis pathways in diabetic nephropathy and chronic kidney disease.

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    • "It is well established that members of the Bcl-2 family are key regulators of cell death. In the present study, a proapoptotic state seems to be favored in the kidney of diabetic ZDF rats, which can lead to loss of renal cells and consequent renal function loss [15, 16]. This increase in cell death by apoptosis appears to be mediated by BAX and Bid. "
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    ABSTRACT: This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood HbA1c levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1β, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1β and TNF-α levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.
    Full-text · Article · Apr 2014 · Mediators of Inflammation
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    • "Failure of current therapeutic approaches to successfully prevent progression of DN in a sizable proportion of patients must be ascribed to an incomplete understanding of the molecular pathways contributing to DN progression. The diabetic microenvironment induces apoptosis in various organs and apoptosis is believed to contribute to the gradual loss of renal function and renal cell mass in DN [3] [4] [5]. Renal tubular epithelial, endothelial and interstitial cell apoptosis is observed in DN [6] [7] [8]. "
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    ABSTRACT: Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and identification of new therapeutic targets is needed. Nicotinamide phosphoribosyltransferase (NAMPT) is both an extracellular and intracellular protein. Circulating NAMPT is increased in diabetics and in chronic kidney disease patients. The role of NAMPT in renal cell biology is poorly understood. NAMPT mRNA and protein were increased in the kidneys of rats with streptozotocin-induced diabetes. Immunohistochemistry localized NAMPT to glomerular and tubular cells in diabetic rats. The inflammatory cytokine TNFα increased NAMPT mRNA, protein and NAD production in cultured kidney human tubular cells. Exogenous NAMPT increased the mRNA expression of chemokines MCP-1 and RANTES. The NAMPT enzymatic activity inhibitor FK866 prevented these effects. By contrast, FK866 boosted TNFα-induced expression of MCP-1 and RANTES mRNA and endogenous NAMPT targeting by siRNA also had a proinflammatory effect. Furthermore, FK866 promoted tubular cell apoptosis in an inflammatory milieu containing the cytokines TNFα/IFNγ. In an inflammatory environment FK866 promoted tubular cell expression of the lethal cytokine TRAIL. These data are consistent with a role of endogenous NAMPT activity as an adaptive, protective response to an inflammatory milieu that differs from the proinflammatory activity of exogenous NAMPT. Thus, disruption of endogenous NAMPT function in stressed cells promotes tubular cell death and chemokine expression. This information may be relevant for the design of novel therapeutic strategies in DN.
    Full-text · Article · Nov 2013 · Biochimica et Biophysica Acta
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    ABSTRACT: Normal kidney structure and function The kidneys maintain the homeostasis of electrolyte, fluid, and acid– base balance; eliminate waste products; and have an endocrine-metabolic function. They secrete hormones such as erythropoietin, Klotho, and 1, 25-(OH)2-vitamin D and clear other hormones and cytokines. Each kidney contains 1 million basic functional units, or nephrons. Each nephron is composed of a glomerulus and a renal tubule. The glomerulus is a tightly woven, highly permeable capillary bed, surrounded by differentiated, very specialized cells, the podocytes. The mesangium contains mesangial cells and holds the capillaries together. Every day, 180 L of plasma is filtered through the glomeruli. Podocytes prevent the filtration of proteins, and their injury will lead to pathological urinary protein excretion (proteinuria). Podocytes do not divide, and podocyte loss causes podocytopenia, an early event in progressive glomerular scarring. Tubular cells reabsorb most of the filtered fluid and nutrients, and only 1 to 2 L of urine is excreted. Proximal tubular cells are responsible for the bulk of reabsorption. They are rich in mitochondria, consume high amounts of energy, and express a variety of transporters that favor the uptake of nephrotoxins. Thus they are prime targets in toxic and ischemic renal injury.
    No preview · Article · Jan 2011
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