Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease.
In autosomal dominant polycystic kidney disease (ADPKD), abnormal proliferation of tubular cells drives cyst development and growth. Sirolimus, an inhibitor of the protein kinase mammalian target of rapamycin (mTOR) and a potent anti-proliferative agent, decreases cyst growth in several genetically distinct rodent models of polycystic kidney disease (PKD). We determined here the effect of sirolimus on renal cyst growth in Pkd2WS25/- mice; an ortholog of human ADPKD involving mutation of the Pkd2 gene. In Pkd2WS25/- mice treated with sirolimus, both the two kidney/total body weight (2K/TBW) ratio and the cyst volume density (CVD) were significantly decreased by over half compared with untreated mice suffering with PKD. However, there was no effect on the increased blood urea nitrogen (BUN) levels as an index of kidney function. There are two distinct complexes containing mTOR depending on its binding partners: mTORC1 and mTORC2. Western blot analysis of whole kidney lysates and immunohistochemistry of the cysts found that phospho-S6 ribosomal protein, a marker of mTORC1 activity, was increased in Pkd2WS25/- mice and its phosphorylation was decreased by sirolimus treatment. Phospho-Akt at serine 473, a marker associated with mTORC2 activity, was not different between Pkd2WS25/- mice and normal littermate controls. Hence, our study found that inhibition of mTORC1 by sirolimus correlated with decreased renal cyst growth in this model of human ADPKD but had no effect on the decline in renal function.
Zafar
Iram
I
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado 80262, USA.
Ravichandran
Kameswaran
K
Belibi
Franck A
FA
Doctor
R Brian
RB
Edelstein
Charles L
CL
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003560:Cysts; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes; D009929:Organ Size / Q000187:drug effects; D016891:Polycystic Kidney, Autosomal Dominant / Q000188:drug therapy*; D011506:Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels / Q000235:genetics
D007166:Immunosuppressive Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels