Diabetes-Induced NF-kB Activation in Renal Cortex: Mechanisms and Consequences.

What is it about?

The study examined the effects of diabetes on NF-kB canonical and noncanonical activation pathways in the renal cortex of diabetic mice. Plasma concentrations of NF-kB-regulated cytokines were increased after one month of hyperglycemia, but most returned to control levels or lower by three months. Cytosolic content of NF-kB canonical pathway proteins did not differ between experimental groups after three months of diabetes, while NF-kB noncanonical pathway proteins were affected, including increased phosphorylation of inhibitor of B kinase-alpha and several fold increases in NF-kB-inducing kinase and RelB, which were predominantly located in tubular epithelial cells. Nuclear content of all NF-kB pathway proteins was decreased by diabetes, with the largest change in RelB and p50. Despite this decrease, measurable increases in protein binding to DNA in diabetic versus control nuclear extracts were observed with electrophoretic mobility shift assay. These results provide evidence for chronic NF-kB activation in the renal cortex of db/db mice and suggest a novel, diabetes-linked mechanism involving both canonical and noncanonical NF-kB pathway proteins. The study also found that numerous cytokines and chemokines were significantly increased in plasma and renal tissue of diabetic mice, including several proinflammatory cytokines, and that these cytokines were decreased 50-80% below controls, while additional cytokines were increased approximately twofold. The nuclear and cytosolic content of NF-kB canonical and noncanonical pathway proteins was decreased in diabetic renal cortex, with RelB increased threefold in the cytoplasm and decreased twofold in the nucleus of diabetic versus control mice. The electrophoretic mobility shift assay showed increased binding of protein to DNA in nuclear extracts of diabetic versus control renal cortex, and antibodies to RelB were capable of supershifting a portion of the protein binding to the DNA. The study suggests that diabetes-induced inflammation and renal cytokine production are linked to chronic activation of the NF-kB pathway, with tubular epithelial cells being the major contributors to total NF-kB protein content and to the diabetes-induced increased cytokine production.

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Why is it important?

This research is important because it provides insights into the mechanisms underlying the chronic activation of the nuclear factor-B (NF-kB) pathway in the renal cortex of diabetic mice. The study highlights the involvement of both canonical and noncanonical NF-kB pathway proteins in diabetes-induced inflammation and renal cytokine production. Key Takeaways: 1. Diabetes-induced inflammation and renal cytokine production are associated with chronic activation of the NF-kB pathway. 2. Both canonical and noncanonical NF-kB pathway proteins are involved in the development of diabetes-induced inflammation and renal cytokine production. 3. Tubular epithelial cells are the primary source of increased cytokine production in diabetic mice. 4. NF-kB activation is associated with increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines in diabetic mice.