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Metformin effectively treats Tsc1 deletion-caused kidney pathology by upregulating AMPK phosphorylation.

ABSTRACT: Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in multiple organs, with most patients developing polycystic kidney disease and leading to a decline of renal function. TSC is caused by loss-of-function mutations in either Tsc1 or Tsc2 gene, but currently, there is no effective treatment for aberrant kidney growth in TSC patients. By generating a renal proximal tubule-specific Tsc1 gene-knockout (Tsc1 ^ptKO) mouse model, we observed that Tsc1 ^ptKO mice developed aberrantly enlarged kidneys primarily due to hypertrophy and proliferation of proximal tubule cells, along with some cystogenesis, interstitial inflammation, and fibrosis. Mechanistic studies revealed inhibition of AMP-activated protein kinase (AMPK) phosphorylation at Thr-172 and activation of Akt phosphorylation at Ser-473 and Thr-308. We therefore treated Tsc1 ^ptKO mice with the AMPK activator, metformin, by daily intraperitoneal injection. Our results indicated that metformin increased the AMPK phosphorylation, but decreased the Akt phosphorylation. These signaling modulations resulted in inhibition of proliferation and induction of apoptosis in the renal proximal tubule cells of Tsc1 ^ptKO mice. Importantly, metformin treatment effectively prevented aberrant kidney enlargement and cyst growth, inhibited inflammatory response, attenuated interstitial fibrosis, and protected renal function. The effects of metformin were further confirmed by in vitro experiments. In conclusion, this study indicates a potential therapeutic effect of metformin on Tsc1 deletion-induced kidney pathology, although currently metformin is primarily prescribed to treat patients with type 2 diabetes.

SUBMITTER: Fang Y

PROVIDER: S-EPMC7295815 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Metformin effectively treats Tsc1 deletion-caused kidney pathology by upregulating AMPK phosphorylation.

Fang Yili Y Li Fang F Qi Chenyang C Mao Xing X Wang Feng F Zhao Zhonghua Z Chen Jian-Kang JK Zhang Zhigang Z Wu Huijuan H

Cell death discovery 20200615

Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in multiple organs, with most patients developing polycystic kidney disease and leading to a decline of renal function. TSC is caused by loss-of-function mutations in either Tsc1 or Tsc2 gene, but currently, there is no effective treatment for aberrant kidney growth in TSC patients. By generating a renal proximal tubule-specific Tsc1 gene-knockout (Tsc1 ptKO) mouse model, we observed ...[more]

PMID: 32566257

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Metformin effectively treats Tsc1 deletion-caused kidney pathology by upregulating AMPK phosphorylation.

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Metformin effectively treats <i>Tsc1</i> deletion-caused kidney pathology by upregulating AMPK phosphorylation.

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