OBJECTIVE: Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, ISN/RPS classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex. METHODS: Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FAS(lpr) (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO-producing enzymes. RESULTS: Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively. CONCLUSION: These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration.
OBJECTIVE:Lupus nephritis (LN) is an immune complex-mediated glomerulonephritis. Proliferative LN (PLN, ISN/RPS classes III and IV)) often leads to renal injury or failure despite traditional induction and maintenance therapy. Successful targeted therapeutic development requires insight into mediators of inflammation in PLN. Superoxide (SO) and its metabolites are mediators of the innate immune response through their ability to mediate reduction-oxidation signaling. Endothelial nitric oxide synthase (eNOS) modulates inflammatory responses in endothelial cells. We hypothesized that markers of SO production would be increased in active PLN and that SO production would be dependent on the activity of select enzymes in the renal cortex. METHODS:Patients with systemic lupus erythematosus were enrolled at the time of renal biopsy for active LN of all classes. Serum collected at baseline was analyzed by HPLC with electrochemical detection for markers of SO production (durable modifications of serum protein Tyr ultimately requiring SO as a substrate). Renal cortex from MRL/MpJ-FAS(lpr) (MRL/lpr) mice with and without functional eNOS was analyzed during active disease for superoxide (SO) production with and without inhibitors of SO-producing enzymes. RESULTS: Serum protein modifications indicative of total SO production were significantly higher in patients with PLN. These markers were increased in association with more active, inflammatory PLN. Mice lacking functional eNOS had 80% higher levels of renal cortical SO during active disease, and inhibitors of nitric oxide synthase and NADPH oxidase reduced these levels by 60% and 77%, respectively. CONCLUSION: These studies demonstrate that SO production is unique to active PLN in a NOS and NADPH oxidase-dependent fashion. These findings suggest the emulating or augmenting eNOS activity or inhibiting NADPH oxidase SO production may be targets of therapy in patients with PLN. The markers of SO production used in this study could rationally be used to select SO-modulating therapies and serve as pharmacodynamic indicators for dose titration.
Authors: Yvonne M W Janssen-Heininger; Brooke T Mossman; Nicholas H Heintz; Henry J Forman; Balaraman Kalyanaraman; Toren Finkel; Jonathan S Stamler; Sue Goo Rhee; Albert van der Vliet Journal: Free Radic Biol Med Date: 2008-03-27 Impact factor: 7.376
Authors: G Moroni; C Novembrino; S Quaglini; R De Giuseppe; B Gallelli; V Uva; V Montanari; P Messa; F Bamonti Journal: Lupus Date: 2009-11-23 Impact factor: 2.911
Authors: Chinedu Njoku; Sally E Self; Philip Ruiz; Ann F Hofbauer; Gary S Gilkeson; Jim C Oates Journal: J Investig Med Date: 2008-10 Impact factor: 2.895
Authors: Onkar Kulkarni; Rahul D Pawar; Werner Purschke; Dirk Eulberg; Norma Selve; Klaus Buchner; Volha Ninichuk; Stephan Segerer; Volker Vielhauer; Sven Klussmann; Hans-Joachim Anders Journal: J Am Soc Nephrol Date: 2007-07-11 Impact factor: 10.121
Authors: Jim C Oates; Viswanathan Ramakrishnan; Paul J Nietert; J David Spence; Thomas W Fleury; Margaret Markiewicz; Dayvia L Russell; Maria F Lopes-Virella Journal: Trans Am Clin Climatol Assoc Date: 2020