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 (Tsc1ptKO) mouse model, we observed that Tsc1ptKO 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 Tsc1ptKO 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 Tsc1ptKO 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.
Highlights
Tuberous sclerosis complex (TSC), a genetic disorder affecting multiple organ systems, is caused by loss-offunction mutations in either TSC1 or TSC2 gene[1]
Sex-matched littermates with a genotype of Tsc1flox/flox;γGT-Cre− were used as control (Fig. S1a)
AMPK inactivation has been observed in multiple diseases, such as enlarged cysts in PKD28, uncontrolled proliferation in breast cancer[23], renal inflammation induced by cyclophosphomide[44], and lung fibrosis after bleomycin stimulation[34]
Summary
Tuberous sclerosis complex (TSC), a genetic disorder affecting multiple organ systems (including the brain, skin, heart, lungs, and kidneys), is caused by loss-offunction mutations in either TSC1 or TSC2 gene[1]. The proteins TSC1 ( known as hamartin) and TSC2 ( called tuberin), which are Official journal of the Cell Death Differentiation Association. TSC patients fail to be diagnosed at the early stage of this disease, with innovative detection technologies, more and more TSC patients are diagnosed with kidney pathology[9]. MTORC1 inhibitors currently used in the clinic seemed to only have a limited cytostatic effect, as the TSC tumors grew again after mTORC1 inhibitors were discontinued, and long-term mTORC1 inhibition could cause detrimental side effects[11,12,13,14,15]. It is noteworthy that deletion of human TSC2 and PKD1 genes results in severe infantile polycystic kidney disease (PKD)—a contiguous gene syndrome[12]. Neither sirolimus (rapamycin) nor everolimus (sirolimus analog) is effective in treating PKD, and these drugs have been reported to cause albuminuria (caused by sirolimus) and leukopenia (caused by everolimus)[16,17,18]
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