Renal disease in tuberous sclerosis complex: pathogenesis and therapy

Lam, Hilaire C.; Siroky, Brian J.; Henske, Elizabeth P.

doi:10.1038/s41581-018-0059-6

Cited by 94 publications

(117 citation statements)

References 138 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The patient who developed bilateral multiple renal cysts in our study also had fragment deletion on TSC2 gene, with his daughter having the same mutation and presenting the same renal lesions. The reasons for TSC patients developing multiple, bilateral RCCs remains unknown, and no other driver mutations have been identified in TSC-associated RCCs [3] . There was also a patient with TSC1 gene mutation had (chromosome 17p13.1) [18] .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different conditions of TSC1/2 genetic mutations

Wang¹,

Zhao²,

Wang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Objective The renal manifestations of tuberous sclerosis complex (TSC) are complicated and various. We’d like to report the information of genetic mutations in TSC patients with renal lesions, and to discuss the relationship between features of renal lesions and genetic mutations, including mutant genes and mutant types. Methods TSC patients with renal lesions who came to Urology Department of our hospital from January 1st, 2015 to January 1st, 2020 were retrospectively analyzed. TSC patients who received next generation sequencing (NGS) of TSC1/2 and imaging examinations were screened out. When familial TSC patients were confirmed, only the probands were included. The patients who had imaging evaluation in our hospital before any treatment for TSC renal angiomyolipomas (AMLs) were also selected for further analysis of relationship between genetic mutations and AML sizes. Results 70 clinically or genetically diagnosed TSC patients with renal lesions were included. The average age was 29.3±8.3 years old. Male-female ratio was 1:1.5. 15 patients (21.4%) were probands of TSC families (3 TSC1 , 10 TSC2 , and 2 NMI). 67 patients (95.8%) had bilateral renal AMLs with one patient had a pathological diagnosis of epithelioid AML ( TSC2 mutation). One patient had multiple renal cysts ( TSC2 mutation), one had renal cell carcinomas (RCCs) ( TSC1 mutation) and one had Wilms tumors ( TSC1 mutation). Among the 70 included patients, 4 patients had TSC1 mutations, 51 had TSC2 mutations, and 15 had no mutation identified (NMI). There was no statistically significant difference between TSC2 mutations and NMI groups (11.4±5.7 vs. 8.0±5.6cm, P = 0.077) when considering AML sizes. There was also no statistically significant difference among AML sizes of patients with TSC2 mutation types of nonsense, missense, frameshift, slipping, and fragment deletion ( P = 0.712). And no statistically significant difference was found between maximus diameters in familial and sporadic patients, either (11.4±5.8 vs. 10.5±5.8, P = 0.663). Conclusions The conditions of TSC genetic mutations will affect type and severity of renal lesions. Other focuses such as protein structure and function need to be studied for renal manifestations. Except for patients with TSC1 and TSC2 genetic mutations, patients with NMI and familial patients are also needed more attention for the pathogenesis of them is still unknown.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Renal lesions are the most common cause of death in adult TSC patients. These renal diseases of TSC may occur in early childhood with progress throughout adulthood [3] . The most common kidney manifestation of TSC is angiomyolipoma (AML), which occurs in 70-90% TSC patients [4] .…”

Section: Introductionmentioning

confidence: 99%

Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different conditions of TSC1/2 genetic mutations

Wang¹,

Zhao²,

Wang³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Mutations of Tsc1 or Tsc2 are associated with an increased tendency to develop renal lesions such as angiomyolipoma, simple multiple cysts, PKD, and renal cell carcinoma. 36,37 Knockout of Tsc1 or Tsc2 in tubular epithelial cells results in aberrant mTORC1 activation, which promotes the proliferation of epithelial cells, renal cyst formation, and renal fibrosis. [37][38][39][40] The present study used mouse models with a conditional deletion of Tsc1 in the proximal tubules to test the hypothesis that mTORC1 activation is involved in the metabolic reprogramming of proximal tubular epithelial cells, and that mTORC1 plays a critical role in renal fibrosis.…”

Section: Translational Statementmentioning

confidence: 99%

Tuberous sclerosis 1 (Tsc1) mediated mTORC1 activation promotes glycolysis in tubular epithelial cells in kidney fibrosis

Cao

Mao

Wen

et al. 2020

Kidney International

View full text Add to dashboard Cite

“…For instance, modulating AMPK has been demonstrated to be an effective maneuver for treating primary breast cancer, ovarian cancer, and inflammatory bowel disease [22][23][24][25] . TSC-associated kidney pathology includes tubulointerstitial fibrosis 11 and decreased apoptosis 26 . Interestingly, pharmacological activation of AMPK has been demonstrated to be an effective strategy for the treatment of mouse Pkd1 deletion-induced PKD 21 .…”

Section: Introductionmentioning

confidence: 99%

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

Fang

Mao

et al. 2020

Cell Death Discov.

View full text Add to dashboard Cite

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.

show abstract

Renal disease in tuberous sclerosis complex: pathogenesis and therapy

Cited by 94 publications

References 138 publications

Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different conditions of TSC1/2 genetic mutations

Analysis of renal lesions in Chinese tuberous sclerosis complex patients with different conditions of TSC1/2 genetic mutations

Tuberous sclerosis 1 (Tsc1) mediated mTORC1 activation promotes glycolysis in tubular epithelial cells in kidney fibrosis

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

Contact Info

Product

Resources

About