Abstract
The disease-modifying effects of target of rapamycin complex 1 (TORC1) inhibitors during different stages of polycystic kidney disease (PKD) are not well defined. In this study, male Lewis Polycystic Kidney Disease (LPK) rats (a genetic ortholog of human NPHP9, phenotypically characterised by diffuse distal nephron cystic growth) and Lewis controls received either vehicle (V) or sirolimus (S, 0.2 mg/kg by intraperitoneal injection 5 days per week) during the early (postnatal weeks 3 to 10) or late stages of disease (weeks 10 to 20). In early-stage disease, sirolimus reduced kidney enlargement (by 63%), slowed the rate of increase in total kidney volume (TKV) in serial MRI by 78.2% (LPK+V: 132.3±59.7 vs. LPK+S: 28.8±12.0% per week) but only partly reduced the percentage renal cyst area (by 19%) and did not affect the decline in endogenous creatinine clearance (CrCl) in LPK rats. In late-stage disease, sirolimus reduced kidney enlargement (by 22%) and the rate of increase in TKV by 71.8% (LPK+V: 13.1±6.6 vs. LPK+S: 3.7±3.7% per week) but the percentage renal cyst area was unaltered, and the CrCl only marginally better. Sirolimus reduced renal TORC1 activation but not TORC2, NF-κB DNA binding activity, CCL2 or TNFα expression, and abnormalities in cilia ultrastructure, hypertension and cardiac disease were also not improved. Thus, the relative treatment efficacy of TORC1 inhibition on kidney enlargement was consistent at all disease stages, but the absolute effect was determined by the timing of drug initiation. Furthermore, cystic microarchitecture, renal function and cardiac disease remain abnormal with TORC1 inhibition, indicating that additional approaches to normalise cellular dedifferentiation, inflammation and hypertension are required to completely arrest the progression of PKDs.
Highlights
The mammalian target of rapamycin complex 1 (TORC1) is an important promoter of cell growth and cyclin D1/pRb activation, and is over-activated in response to mutational dysfunction of cilia-associated proteins in polycystic kidney disease (PKD) [1], [2], [3] [4]
In Lewis rats, p-4E-BP1 was strongly expressed in cortical tubules and moderate in medullary tubules, and this pattern of expression remained consistent from weeks 1 to 20 (Fig 1, middle panel)
2, most likely because the kidney size was smaller at the time of commencing treatment. These results were contrary to our initial hypothesis, as in previous studies we showed that the intensity of proliferation is highest week 3 in Lewis Polycystic Kidney Disease (LPK) rats [13], and surmised that all of the treatment effects of sirolimus on kidney enlargement might be largely restricted to when treatment was commenced in the early phase of disease
Summary
The mammalian target of rapamycin complex 1 (TORC1) is an important promoter of cell growth and cyclin D1/pRb activation, and is over-activated in response to mutational dysfunction of cilia-associated proteins in polycystic kidney disease (PKD) [1], [2], [3] [4]. In some animal models, the expression of TORC1 and cell cycle proteins as well as CEC proliferation exhibit time-dependent changes [13, 14], suggesting that there might be a therapeutic window in which anti-proliferative inhibitors are most effective in preventing kidney enlargement in certain types of PKDs [13]. Another proposed mechanism by which sirolimus could reduce kidney enlargement is the regression of renal cyst growth [7, 8], but the underlying mechanisms and therapeutic significance of this are not certain. The effects on renal function, cilia morphology and cardiovascular disease have not been fully assessed in previous preclinical studies [18]
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