Renal-specific oxido-reductase (RSOR), an enzyme relevant to diabetic nephropathy, is exclusively expressed in renal tubules. Studies were initiated to determine whether, like other tubular specific proteins, it selectively modulates tubulogenesis. Northern blot analyses revealed a -1.5 kb transcript, and RSOR expression was detectable in mice embryonic kidneys at day-13, gradually increased by day-17 and extended into neo- and post-natal periods. RSOR mRNA and protein expression was confined to proximal tubules, commencing at day-17 and increasing subsequently, but remained absent in glomeruli and medulla. Treatment with RSOR antisense oligodeoxynucleotide resulted in a dose-dependant dysmorphogenesis of metanephric explants harvested at day-13. The explants were smaller, had expanded mesenchyme, and the population of tubules was markedly decreased. The glomeruli were unaffected, as assessed by mRNA expression of glomerular epithelial protein1 and reactivity with wheat germ agglutinin. Antisense treatment led to a selective reduction of RSOR mRNA. Immunoprecipitation also indicated a selective translational blockade of RSOR. These findings suggest that RSOR is developmentally regulated, exhibits a distinct spatio-temporal distribution and probably plays a role in tubulogenesis.