Evidence for pericyte origin of TSC-associated renal angiomyolipomas and implications for angiotensin receptor inhibition therapy

Siroky, Brian J.; Yin, Hong; Dixon, Bradley P.; Reichert, Ryan; Hellmann, Anna R.; Ramkumar, Thiruvamoor; Tsuchihashi, Zenta; Bunni, Marlene A.; Dillon, J. C.; Bell, P. Darwin; Sampson, Julian R.; Bissler, John J.

doi:10.1152/ajprenal.00569.2013

Cited by 47 publications

(29 citation statements)

References 53 publications

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“…Recent evidence suggests that angiomyolipomata arise from a subpopulation of renal vascular pericytes (Siroky et al. ); therefore, we used the Ren1cCre to disrupt the floxed Tsc1 allele ( Ren1cCreTsc1 ). Although Ren1cCre recombinase is expressed in the renal pericyte compartment, the animals most often develop cystic disease.…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

et al. 2019

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Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.

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Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

et al. 2019

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“…VEGF-D has been proposed a potential biomarker of lymphangioleiomyomatosis severity and treatment response(32). Recent work indicates that both VEGF-A and VEGF-D can be detected in the sera of TSC patients (33). Taken together, these results indicate the similar mechanisms may be at play in tumorogenesis in Tsc1 cc Darpp-32-Cre+ mouse as in patients with TSC.…”

Section: Discussionmentioning

confidence: 99%

A Vascular Model of Tsc1 Deficiency Accelerates Renal Tumor Formation with Accompanying Hemangiosarcomas

Leech

Lammers

Goldman

et al. 2015

Molecular Cancer Research

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Tuberous Sclerosis Complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Since paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug-testing for therapies of TSC related tumors.

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“…This analysis was the first to examine multiple angiogenesis‐related biomarkers in TSC patients with angiomyolipomas and to investigate the association of everolimus treatment with circulating biomarker levels. Circulating levels of VEGF‐A, VEGF‐D, COL‐IV and sVEGFR2 have previously been found to be increased in patients with angiomyolipomas associated with TSC, reflecting the vascular pericytic origins of angiomyolipoma lesions . In EXIST‐2, the observed decrease in VEGF‐D, COL‐IV and sVEGFR2 levels and concomitant increase in VEGF‐A levels from baseline in the patients treated with everolimus supports the hypothesis that everolimus may, at least partially, act through an anti‐angiogenic mechanism in these patients.…”

Section: Discussionmentioning

confidence: 99%