Circulating factor in patients with recurrent focal segmental glomerulosclerosis postrenal transplantation inhibits expression of inducible nitric oxide synthase and nitric oxide production by cultured rat mesangial cells.
BACKGROUND
Primary focal segmental glomerulosclerosis (FSGS) recurs in nearly 30% of patients who progress to end-stage renal disease and then receive a kidney transplant. A circulating plasma factor has been isolated from these patients that increases glomerular permeability to albumin in vitro. Because of the pivotal role of the mesangial cell in the accumulation of extracellular matrix (ECM) material within the glomerulus and the modulation of matrix protein synthesis by nitric oxide (NO), we examined the effect of the FSGS factor on inducible nitric oxide synthase (iNOS) expression and NO production by cultured rat mesangial cells (RMC).


METHODS
RMC were incubated with the supernatant following 70% ammonium sulfate precipitation of serum from patients with recurrent FSGS.


RESULTS
Addition of the FSGS factor to cultured RMC led to a significant inhibition of nitrite accumulation, an index of NO synthesis. There was a parallel decline in iNOS gene and protein expression. Sera obtained from control patients or those with minimal change nephrotic syndrome or diabetic nephropathy that was processed in the same manner as FSGS samples had no effect NO synthesis or iNOS activity. The inhibitory effect of the FSGS factor on NO production persisted despite addition of indomethacin (0.1-1 mumol/L) or cyclosporine (25 micrograms/mL) to test media.


CONCLUSIONS
These data indicate that the FSGS factor independently alters two aspects of glomerular function--permselectivity and matrix protein synthesis--by distinct mechanisms. FSGS factor-induced disturbances in iNOS gene and protein expression and NO production by mesangial cells may antagonize the antifibrotic effect of NO within the mesangium and contribute to progressive glomerulosclerosis in patients with primary FSGS.
Trachtman
H
H
Department of Pediatrics, Schneider Children's Hospital, New Hyde Park, NY 11040-1432, USA.
Futterweit
S
S
Singhal
P C
PC
Franki
N
N
Sharma
M
M
Sharma
R
R
Savin
V
V
D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology*; D002470:Cell Survival; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000097:blood* / Q000209:etiology; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010956:Plasmapheresis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012008:Recurrence
D001798:Blood Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; D016572:Cyclosporine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007213:Indomethacin