Gene expression of 5-lipoxygenase and LTA(4) hydrolase in renal tissue of nephrotic syndrome patients

Leukotrienes (LT) of the 5-lipoxygenase pathway constitute a class of poten t biological lipid mediators of inflammation implicated in the pathogenesis of different models of experimental glomerulonephritis. The key enzyme, 5- lipoxygenase (5-LO), catalyses oxygenation of arachidonic acid to generate the primary leukotriene LTA(4). This LT, in turn, serves as a substrate for either LTA(4) hydrolase, to form the potent chemoattractant LTB4, or LTC4 synthase, to produce the powerful vasoconstrictor LTC4. To investigate the potential role of LT in the pathogenesis of human glomerulonephritis with n ephrotic syndrome, we examined the gene expression of 5-LO and LTA(4) hydro lase in renal tissue of 21 adult patients with nephrotic syndrome and 11 co ntrols. The patients consisted of 11 cases of membranous nephropathy (MN), seven focal and segmental glomerulosclerosis (FSGS), two non-IgA mesangial glomerulonephritis and one minimal change disease. Total RNA purified from renal tissue was reverse transcribed into cDNA and amplified with specific primers in a polymerase chain reaction (RT-PCR). Eight patients' renal tiss ue, four MN and four FSGS, co-expressed 5-LO and LTA(4) hydrolase. In situ hybridization analysis revealed 5-LO expression and distribution limited to the interstitial cells surrounding the peritubular capillaries. Comparativ e clinical and immunohistological data showed that these eight patients had impaired renal function and interstitial changes that significantly correl ated with 5-LO expression. These findings suggest that leukotrienes may pla y an important role in the pathogenesis of MN and FSGS. These results are a lso relevant to elucidating the pathophysiologic mechanisms which underlie progression to renal failure in these diseases.