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Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a downstream pathway of mTOR, as a new therapeutic target for PKD. We generated zebrafish mutants for pkd1 and noted cystic kidney and mTOR activation in pkd1a mutants, suggesting a conserved ADPKD model. Further assessment of the mutants revealed impaired autophagic flux, which was conserved in kidney epithelial cells derived from both Pkd1-null mice and ADPKD patients. We found that inhibition of autophagy by knocking down the core autophagy protein Atg5 promotes cystogenesis, while activation of autophagy using a specific inducer Beclin-1 peptide ameliorates cysts in the pkd1a model. Treatment with compound autophagy activators, including mTOR-dependent rapamycin as well as mTOR-independent carbamazepine and minoxidil, markedly attenuated cyst formation and restored kidney function. Finally, we showed that combination treatment with low doses of rapamycin and carbamazepine was able to attenuate cyst formation as effectively as a single treatment with a high dose of rapamycin alone. In summary, our results suggested a modifying effect of autophagy on ADPKD, established autophagy activation as a novel therapy for ADPKD, and presented zebrafish as an efficient vertebrate model for developing PKD therapeutic strategies.

SUBMITTER: Zhu P

PROVIDER: S-EPMC6251521 | biostudies-other | 2017 Jan

REPOSITORIES: biostudies-other

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Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model.

Zhu Ping P Sieben Cynthia J CJ Xu Xiaolei X Harris Peter C PC Lin Xueying X

Human molecular genetics 20170101 1

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2. It is one of the most common heritable human diseases with eventual development of renal failure; however, effective treatment is lacking. While inhibition of mechanistic target of rapamycin (mTOR) effectively slows cyst expansions in animal models, results from clinical studies are controversial, prompting further mechanistic studies of mTOR-based therapy. Here, we aim to establish autophagy, a d ...[more]

PMID: 28007903

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Project description:Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin-angiotensin-aldosterone system, and progression of kidney disease.In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m(2) of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting-enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume.The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P=0.006), without significant differences between the lisinopril-telmisartan group and the lisinopril-placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P=0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (-1.17 vs. -0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P=0.002).In early ADPKD, the combination of lisinopril and telmisartan did not significantly alter the rate of increase in total kidney volume. As compared with standard blood-pressure control, rigorous blood-pressure control was associated with a slower increase in total kidney volume, no overall change in the estimated GFR, a greater decline in the left-ventricular-mass index, and greater reduction in urinary albumin excretion. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study A] ClinicalTrials.gov number, NCT00283686.).

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Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model.

Publications

Autophagy activators suppress cystogenesis in an autosomal dominant polycystic kidney disease model.

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