Tumor necrosis factor induces sodium retention in diabetic rats through sequential effects on distal tubule cells

DiPetrillo, Keith; Coutermarsh, Bonita; Soucy, Nicole V.; Hwa, John; Gesek, F. A.

doi:10.1111/j.1523-1755.2004.00606.x

Cited by 34 publications

(31 citation statements)

References 38 publications

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“…Additionally, many studies have shown that changes in hormone levels, vasoactive peptides, cytokine, and growth factors are associated with diabetic nephropathy development and progression. Specifically, rat studies have suggested a functional role for the proinflammatory cytokine tumor necrosis factor (TNF)-␣ in the pathogenesis of diabetic nephropathy (19,20). Supporting this finding are intervention studies in patients with either diabetic or membranous nephropathy that found that the nonspecific TNF-␣ inhibitor pentoxifylline reduced both TNF-␣ and urinary proteinura (21,22).…”

Section: Drb1*04 and Reduced Diabetic Nephropathysupporting

confidence: 52%

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

et al. 2008

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OBJECTIVE—The purpose of this study was to examine whether known genetic risk factors for type 1 diabetes (HLA-DRB1, -DQA1, and -DQB1 and insulin locus) play a role in the etiology of diabetic nephropathy. RESEARCH DESIGN AND METHODS—Genetic analysis of HLA-DRB1, -DQA1, -DQB1 and the insulin gene (INS) was performed in the Genetics of Kidneys in Diabetes (GoKinD) collection of DNA (European ancestry subset), which includes case patients with type 1 diabetes and nephropathy (n = 829) and control patients with type 1 diabetes but not nephropathy (n = 904). The availability of phenotypic and genotypic data on GoKinD participants allowed a detailed analysis of the association of these genes with diabetic nephropathy. RESULTS—Diabetic probands who were homozygous for HLA-DRB1*04 were 50% less likely to have nephropathy than probands without any DRB1*04 alleles. In heterozygous carriers, a protective effect of this allele was not as clearly evident; the mode of inheritance therefore remains unclear. This association was seen in probands with both short (<28 years, P = 0.02) and long (≥28 years, P = 0.0001) duration of diabetes. A1C, a marker of sustained hyperglycemia, was increased in control probands with normoalbuminuira, despite long-duration diabetes, from 7.2 to 7.3 to 7.7% with 0, 1, and 2 copies of the DRB1*04 allele, respectively. This result is consistent with a protective effect of DRB1*04 that may allow individuals to tolerate higher levels of hyperglycemia, as measured by A1C, without developing nephropathy. CONCLUSIONS—These data suggest that carriers of DRB1*04 are protected from some of the injurious hyperglycemic effects related to nephropathy. Interestingly, DRB1*04 appears to be both a risk allele for type 1 diabetes and a protective allele for nephropathy.

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Section: Drb1*04 and Reduced Diabetic Nephropathysupporting

confidence: 52%

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

et al. 2008

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“…TNF␣ has also been shown to increase AFC during acute bacterial pneumonia (31) and intestinal reperfusion (32). Acute TNF␣ stimulation also induces sodium retention in diabetic rats (33). This sodium retention is blocked by amiloride, indicating that this sodium retention is mediated by ENaC.…”

Section: Figmentioning

confidence: 93%

IκB Kinase-β (IKKβ) Modulation of Epithelial Sodium Channel Activity

Lebowitz

Edinger

et al. 2004

Journal of Biological Chemistry

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Using the yeast two-hybrid system, we identified a number of proteins that interacted with the carboxyl termini of murine epithelial sodium channel (ENaC) subunits. Initial screens indicated an interaction between the carboxyl terminus of ␤-ENaC and I B kinase-␤ (IKK␤), the kinase that phosphorylates I ␤ and results in nuclear targeting of NF-B. A true two-hybrid reaction employing full-length IKK␤ and the carboxyl termini of all three subunits confirmed a strong interaction with ␤-ENaC, a weak interaction with ␥-ENaC, and no interaction with ␣-ENaC. Co-immunoprecipitation studies for IKK␤ were performed in a murine cortical collecting duct cell line that endogenously expresses ENaC. Immunoprecipitation with ␤-ENaC, but not ␥-ENaC, resulted in co-immunoprecipitation of IKK␤. To examine the direct effects of IKK␤ on ENaC activity, co-expression studies were performed using the two-electrode voltage clamp technique in Xenopus oocytes. Oocytes were injected with cRNAs for ␣␤␥-ENaC with or without cRNA for IKK␤. Co-injection of IKK␤ significantly increased the amiloride-sensitive current above controls. Using cell surface ENaC labeling, we determined that an increase of ENaC in the plasma membrane accounted for the increase in current. The injection of kinase-dead IKK␤ (K44A) in ENaC-expressing oocytes resulted in a significant decrease in current. Treatment of mpkCCD c14 cells with aldosterone increased whole cell amounts of IKK␤. Because this result suggested that aldosterone might activate NF-B, mpkCCD c14 cells were transiently transfected with a luciferase reporter gene responsive to NF-B activation. Both aldosterone and tumor necrosis factor-␣ (TNF␣) stimulation caused a similar and significant increase in luciferase activity as compared with controls. We conclude that IKK␤ interacts with ENaC by up-regulating ENaC at the plasma membrane and that the presence of IKK␤ is at very least permissive to ENaC function. These studies also suggest a previously unexpected interaction between the NF-B transcription pathway and steroid regulatory pathways in epithelial cells.

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“…IL-1beta and IL-6 increase vascular endothelial permeability and alter ECM dynamics at both the mesangial and podocyte levels, contributing to interstitial infi ltrates, glomerular basement membrane thickening, mesangial expansion, and tubula r atrophy (Pecoits-Filho et al, 2002;Dalla et al, 2005). TNF-alpha is cytotoxic to renal cells and contributes to sodium retention and renal hypertrophy, alterations that are observed during the earlier stages of DN (DiPetrillo et al, 2004). Also, the exposure of tubular epithelial cells to TNF-alpha results in a significant increase in the synthesis and secretion of lymphocyte-and neutrophil-chemoattractant factors, and in the cell surface expression of ICAM-1 (Ishikura et al, 1991).…”

Section: Pathophysiological Features Of Diabetic Nephro-pathymentioning

confidence: 99%

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

Ezquer

Arango-Rodríguez

et al. 2012

Biol. Res.

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Currently, one of the main threats to public health is diabetes mellitus. Its most detrimental complication is diabetic nephropathy (DN), a clinical syndrome associated with kidney damage and an increased risk of cardiovascular disease. Irrespective of the type of diabetes, DN follows a well-known temporal course. The earliest detectable signs are microalbuminuria and histopathological changes including extracellular matrix deposition, glomerular basement membrane thickening, glomerular and mesangial expansion. Later on macroalbuminuria appears, followed by a progressive decline in glomerular fi ltration rate and the loss of glomerular podocytes, tubulointerstitial fi brosis, glomerulosclerosis and arteriolar hyalinosis. Tight glycemic and hypertension controls remain the key factors for preventing or arresting the progression of DN. Nevertheless, despite considerable educational eff ort to control the disease, a signifi cant number of patients not only develop DN, but also progress to chronic kidney disease. Therefore, the availability of a strategy aimed to prevent, delay or revert DN would be highly desirable. In this article, we review the pathophysiological features of DN and the therapeutic mechanisms of multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs). The perfect match between them, together with encouraging pre-clinical data available, allow us to support the notion that MSC transplantation is a promising therapeutic strategy to manage DN onset and progression, not only because of the safety of this procedure, but mainly because of the renoprotective potential of MSCs.

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Tumor necrosis factor induces sodium retention in diabetic rats through sequential effects on distal tubule cells

Cited by 34 publications

References 38 publications

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

Nephropathy in Type 1 Diabetes Is Diminished in Carriers of HLA-DRB1*04

IκB Kinase-β (IKKβ) Modulation of Epithelial Sodium Channel Activity

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

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