High concentrations of nitric oxide (NO), produced by the inducible form of nitric oxide synthase, expressed by proximal tubular (PT) cells and invading macrophages, may damage the PT during inflammatory renal disease. The natriuretic peptide hormones (NPs) regulate inducible NO production in a variety of cell types. The aim of our studies was to investigate the regulation of inducible NO synthesis in macrophages and PT cells by the NPs. Cultures of rat and human PT cells and murine macrophages cell lines were incubated with combinations of cytokines and/or lipopolysaccharide (LPS) (to stimulate NO synthesis), NPs and pharmacological agents. Nitrite was measured as an indicator of NO production using the Griess assay. To investigate more directly the possibility of regulation of NP production by NP mediated interactions between PT cells and macrophages we exposed LPS treated macrophages to RPT cell supernatant, which contained endogenous NPs. Our studies demonstrated that exogenous NPs had no effects on the NO production of cytokine/LPS stimulated PT cells. However, the NPs increased the NO production of LPS treated macrophages via NPRs -A and -B, and the production of cyclic guanine monophosphate (cGMP) and subsequent activation of cGMP dependent protein kinase. Paradoxically, endogenous NPs, contained within RPT cell supernatant, inhibited the NO production of LPS treated macrophages, suggesting that other RPT cell derived factors primed the macrophages to respond to the NPs by decreasing NO production. In conclusion our results suggest that NP mediated PT cell/macrophage interactions may regulate the inducible NO production of activated macrophages, but not PT cells, during tubulointerstitial inflammation. PT cells may produce factors that facilitate NP mediated inhibition of macrophage. NO synthesis as well as being sources of NPs. Therefore NP mediated PT cell/macrophage interactions that inhibit macrophage NO synthesis may be an important protective mechanism during tubulointerstitial inflammation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:401479 |
| Date | January 2003 |
| Creators | Espie, Gordon |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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