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2.
Sci Transl Med ; 11(476)2019 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-30674655

RESUMO

Fibrosis contributes to the progression of chronic kidney disease (CKD). Severe acute kidney injury can lead to CKD through proximal tubular cell (PTC) cycle arrest in the G2-M phase, with secretion of profibrotic factors. Here, we show that epithelial cells in the G2-M phase form target of rapamycin (TOR)-autophagy spatial coupling compartments (TASCCs), which promote profibrotic secretion similar to the senescence-associated secretory phenotype. Cyclin G1 (CG1), an atypical cyclin, promoted G2-M arrest in PTCs and up-regulated TASCC formation. PTC TASCC formation was also present in humans with CKD. Prevention of TASCC formation in cultured PTCs blocked secretion of profibrotic factors. PTC-specific knockout of a key TASCC component reduced the rate of kidney fibrosis progression in mice with CKD. CG1 induction and TASCC formation also occur in liver fibrosis. Deletion of CG1 reduced G2-M phase cells and TASCC formation in vivo. This study provides mechanistic evidence supporting how profibrotic G2-M arrest is induced in kidney injury and how G2-M-arrested PTCs promote fibrosis, identifying new therapeutic targets to mitigate kidney fibrosis.

3.
Nature ; 558(7711): 540-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899452

RESUMO

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

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