Effects of TORC1 Inhibition during the Early and Established Phases of Polycystic Kidney Disease

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.

The protective effects of ischemic preconditioning on rats with renal ischemia-reperfusion injury and the effects on the expression of Bcl-2 and Bax

“…Studies have shown that renal ischemia for more than 20 min will cause damage, ischemia for 20–40 min is reversible, but reperfusion after ischemia for more than 40 min can cause permanent damage ( 3 ). Studies have shown that the development of tolerance of organs to ischemia can inhibit or reduced the ischemia-reperfusion injury ( 4 ). Takahashi-Sato et al ( 5 ) carried out a study to explore the effects of different preconditioning and postconditioning methods on ischemia/reperfusion in the heart.…”

Mixed-Unit Lattice Approach for Area Determination of Cellular and Subcellular Structures

“…In PKD, expansion of fluid-filled cysts drives an increase in total kidney volume (TKV) [5]. A number of studies [13][14][15] have shown that increasing TKV corresponds to a more rapid decline in renal dysfunction. Measurement of the cystic index (i.e., the ratio of cystic area or cystic volume to renal parenchymal area or TKV, respectively) is critical to inform of disease progression [5].…”

“…Measurement of the cystic index (i.e., the ratio of cystic area or cystic volume to renal parenchymal area or TKV, respectively) is critical to inform of disease progression [5]. Furthermore, at least in preclinical PKD models, the efficacy of a number of therapeutic strategies is determined by the ability of these regimens to retard the progressive increase in cystic index [13][14][15]. Measurement of the cystic area and time-dependent changes therein is therefore critical to inform of both disease status and drug efficacy.…”

<p>Regression of Peritubular Capillaries Coincides with Angiogenesis and Renal Cyst Growth in Experimental Polycystic Kidney Disease</p>

“…13 To our knowledge the longitudinal changes in angiogenesis and peritubular capillary loss, and their relationship to cyst formation have not been evaluated in experimental models of PKD. Furthermore, in previous studies we and others have shown the mammalian target of rapamycin (mTOR) inhibitor, sirolimus attenuates kidney cyst growth in experimental PKD, 14,15 but experimental studies in liver and colon cancer suggest that it also has anti-angiogenic properties. 16,17 Therefore, the aim of this study was to test the following hypotheses: (i) angiogenesis is coupled with kidney cyst expansion, and the loss of peritubular capillary networks which precedes the onset of interstitial fibrosis; and (ii) sirolimus reduces angiogenesis in PKD.…”