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Nitric oxide mediates immunologic injury to kidney mesangium in experimental glomerulonephritis
I Narita1, W A Border, M Ketteler
1Division of Nephrology, University of Utah School of Medicine, Salt Lake City.
Background:
Nitric oxide (NO), produced from L-arginine by an inducible NO synthase, is an important effector molecule in inflammatory and immunologic tissue injury. The role of NO generation in immunologic injury to glomerular mesangial cells and the effect of dietary restriction of L-arginine on this injury was investigated.
Experimental Design:
Acute glomerulonephritis was induced by injection of anti-thymocyte serum (ATS) which binds to an antigen on the glomerular mesangial cell. Complement-mediated mesangial cell lysis follows. The effect of blocking NO production in vivo by administration of the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) 60 minutes before ATS injection on mesangial cell lysis, and on the severity of disease was assessed. The effect of dietary restriction of L-arginine on mesangial cell lysis in response to ATS injection was also determined.
Results:
We report here that blocking NO production in vivo with L-NMMA prevented mesangial cell lysis by 90%. Injection of L-NMMA caused transiently elevated systolic blood pressure, but did not diminish ATS binding to mesangial cells or recruitment of monocyte/macrophages into glomeruli indicating that L-NMMA pretreatment did not limit injury by insufficient glomerular perfusion. ATS-induced proteinuria and increases in urinary nitrite excretion were prevented. Glomerular expression of transforming growth factor-beta and accumulation of extracellular matrix were suppressed by the L-NMMA treatment. Low protein diet (6%), but also selective dietary L-arginine restriction, given for 7 days before induction of the disease mimicked L-NMMA treatment, significantly decreasing mesangial cell lysis. The effect of a low protein diet was abolished by dietary L-arginine supplementation.
Conclusions:
This study strongly implicates NO as a mediator in immune-mediated mesangial cell lysis. The data suggest that limiting NO production by limiting arginine intake might decrease glomerular injury and subsequent glomerulosclerosis.