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      Regulation of Tubular Cell MCP-1 Production by Intracellular Ions: A Role for Sodium and Calcium

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      Cardiorenal Medicine
      S. Karger AG
      Sodium, Calcium, pH, Chemokine, Proximal tubule

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          Proximal tubule cells (PTC) in chronic renal disease produce chemokines which cause renal interstitial inflammation, and also transport more Na<sup>+</sup> than normal. To investigate whether these two events might be related, monocyte chemoattractant protein-1 (MCP-1) production was examined in rat PTC in primary culture. Amiloride reduced, while ouabain increased levels of MCP-1 mRNA and protein. Amiloride reduced MCP-1 in cells stimulated with ouabain, lipopolysaccharide (LPS) or albumin. Intracellular Na<sup>+</sup> rose with ouabain, but not LPS or albumin. Effects of amiloride, ouabain, LPS and albumin were abrogated by sodium-free but not chloride-free culture medium, and were not explained by changes in intracellular pH. Intracellular Ca<sup>2+</sup> rose with ouabain, LPS or albumin and sodium-free medium. BAPTA-AM reduced intracellular Ca<sup>2+</sup> and MCP-1 mRNA levels in unstimulated cells, and cells stimulated with ouabain, LPS or albumin. Thus, amiloride and ouabain may alter tubular cell MCP-1 by changing intracellular Na<sup>+</sup>, with secondary changes in intracellular Ca<sup>2+</sup>, whereas stimulation by LPS and albumin may involve Ca<sup>2+</sup> directly.

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          Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation.

          Abnormal traffic of proteins through the glomerular capillary has an intrinsic renal toxicity possibly linked to the subsequent process of proximal tubular reabsorption. Here we investigated in vitro the effect of protein overload on proximal tubular cell production of RANTES, a nuclear factor-kappa B (NF-kappa B)-dependent chemokine with potent chemotactic activity for monocytes/macrophages and T lymphocytes. Confluent pig LLC-PK1 cells were incubated for 24 and 48 hours with Eagle's MEM plus 0.5% FCS containing bovine serum albumin (BSA, 1 to 30 mg/ml). Tumor necrosis factor-alpha (TNF-alpha; 100 U/ml) was used as a positive control. RANTES was measured in cell supernatants by ELISA. Bovine serum albumin (BSA) induced a time- and dose-dependent increase in proximal tubular cell RANTES production. Selected experiments using transwells showed that the RANTES release was predominantly basolateral. The stimulatory effect on tubular RANTES was not specific to albumin but was shared by immunoglobulin (Ig) G. We then explored the role of NF-kappa B on BSA-induced RANTES. The NF-kappa B inhibitors pyrrolidine dithiocarbamate (PDTC; 25 microM) and sodium salicylate (10 mM) significantly reduced BSA-induced RANTES production. Electrophoretic mobility shift assay of nuclear extracts of LLC-PK1 exposed to BSA revealed an intense NF-kappa B activation as early as 30 minutes in a dose-dependent fashion, which was inhibited by PDTC. Supershift analysis revealed that the protein subunits of activated NF-kappa B were p65/p65 homodimer, p65/cRel, p50/p65 heterodimers. Given its chemotactic activity, RANTES released into the interstitium might promote inflammatory cell recruitment and contribute to interstitial inflammation and renal disease progression.

            Author and article information

            Nephron Exp Nephrol
            Cardiorenal Medicine
            S. Karger AG
            June 2001
            23 April 2001
            : 9
            : 3
            : 205-213
            Department of Renal Medicine, The University of Sydney at Westmead Hospital, Westmead, N.S.W., Australia
            52613 Exp Nephrol 2001;9:205–213
            © 2001 S. Karger AG, Basel

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            Page count
            Figures: 7, Tables: 2, References: 26, Pages: 9
            Self URI (application/pdf): https://www.karger.com/Article/Pdf/52613
            Self URI (text/html): https://www.karger.com/Article/FullText/52613
            Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
            Original Paper

            Cardiovascular Medicine,Nephrology
            Sodium,Calcium,pH,Chemokine,Proximal tubule
            Cardiovascular Medicine, Nephrology
            Sodium, Calcium, pH, Chemokine, Proximal tubule


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