Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease

摘要

The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 weeks, followed by 7 weeks without treatment, or continuously for 12 weeks. Removal of everolimus did not result in the appearance of renal cysts up to 7 week post-withdrawal despite the re-emergence of the S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in a striking non-cystic renal parenchyma enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regiments ameliorated kidney function, preserved glomerular-tubular connection and reduced proteinuria. Pulse treatment in the early age delays cyst development but leads to striking glomerular hypertrophy which might have a major impact on the treatment of patients with autosomal dominant polycystic kidney disease. Key words: mammalian target of rapamycin (mTOR), everolimus, polycystic kidney disease.