Cytokine-stimulated nitric oxide production in the human renal proximal tubule and its modulation by natriuretic peptides: A novel immunomodulatory mechanism?

Although the importance of the human kidney in a variety of disease states is well recognised, the exact mechanisms involved remain unclear. Animal di sease models suggest that while high local concentrations of nitric oxide ( NO) may play a key role in the initiation and progression of renal disease, low levels may also be essential for normal renal function and cell protec tion, possibly explaining the variable reports of both beneficial and detri mental responses of renal disease models following NO inhibition. NO has bo th physiological and pathological roles and clearly a balance between these two primary roles is likely to prevail leading to the conclusion that part ial rather than total inhibition of NO production may be beneficial. Despit e increasing evidence for the role of NO from animal disease models, little is known of the role of NO and potential modulators within the human kidne y. In this review we describe three series of studies during which we exami ned the ability of primary cultures of human proximal tubular cells to prod uce NO in response to inflammatory cytokines and the possible role of poten tial modulators such as the natriuretic peptides. Following challenge with the combination of inflammatory cytokines IL-1 beta, TNF-alpha, and IFN-gam ma, such cultures exhibit a time-dependent increase in inducible NO synthet ase induction and corresponding NO production, an effect which was inhibite d by L-NMMA. In the second series of studies we demonstrated that increasin g concentrations of atrial natriuretic factor (ANF) or C((4-23))ANF could s timulate a time- and concentration-dependent increase in nitric oxide produ ction which was again abolished by L-NMMA. These results suggested that ANF acting at the natriuretic peptide receptor C could stimulate nitric oxide production in human proximal tubular cells. In the final series of studies we demonstrated that pro-inflammatory cytokine-induced nitric oxide product ion could be inhibited by ANF, brain naturetic peptide, C-type natriuretic peptide or C((4-23))ANF The actions of the natriuretic peptides and C((4-23 ))ANF was to return pro-inflammatory nitric oxide production to those obser ved when human proximal tubular cells were incubated with ANF alone indicat ing that this inhibition was mediated via the natriuretic peptide receptor C. The function of NO in the kidney is unclear but undoubtedly it has both beneficial and detrimental actions which in health remain in balance. Howev er, when the kidney is subjected to an immune challenge, high cytotoxic lev els of NO are produced locally and appear to be responsible for local damag e, unfortunately fetal inhibition of NO production during such disease stat es does not always result in benefit. Clearly total abolition of an NO resp onse removes important integral protective actions such as vasodilation. In the ideal situation, treatment of disease processes related to NO excess w ould involve the inhibition of these high local levels while still protecti ng vital dependent mechanisms. We believe that the NO natriuretic peptide i nteraction, which we have reported in this review, places ANF in a unique p osition of being able to maintain the essential or protective actions of NO while inhibiting potentially cytotoxic or detrimental effects. Copyright ( C) 1999 S. Karger AG, Basel.