Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond

Abstract

The renal manifestations of tuberous sclerosis complex (TSC) are remarkably diverse, including polycystic kidney disease, oncocytomas, renal cell carcinomas, and both benign and malignant angiomyolipomas. All of these occur in children as well as adults with TSC. Benign angiomyolipomas, which can cause spontaneous life-threatening hemorrhage, are by far the most prevalent and the greatest source of morbidity. What is particularly unusual about TSC, setting it apart from virtually all other inherited forms of renal disease, is the abnormalities of both mesenchymal cells (angiomyolipomas) and epithelial cells (cysts, oncocytomas, and carcinomas). Recently, the TSC1/TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin). This places TSC1/TSC2 at center stage in signaling pathways that regulate cell growth. Furthermore, recent advances in TSC1/TSC2 signaling open the door for targeted therapy for TSC patients. Here, we will address the genetic, cellular and biochemical mechanisms that may contribute to the unusually broad spectrum of renal disease in cells with TSC1 or TSC2 mutations, and consider how the TSC signaling pathways may be linked to other renal diseases such as polycystic kidney disease and renal cell carcinoma.

Epithelioid angiomyolipoma of the kidney: pathological features and clinical outcome in a series of consecutively resected tumors

“…23 Cysts and multiple AMLs are the most common renal manifestation in TSC. 24,25 In our series, only three cases (#1, 2, and 16) had other concurrent renal tumors. In two of these, one additional classical AML each was present; however, no evidence of tuberous sclerosis syndrome was documented in these two.…”

Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2

“…However, the kidney adenomas that develop in their Tsc2 +/− mice, as in ours, are not accelerated by Pten haploinsufficiency. It should be noted that, while these kidney adenomas share a location with human TSC tumors, they are not related to the kidney angiomyolipomas (AMLs) most common in TSC patients (>80%) (Henske 2005). AMLs more closely resemble the hemangiomas found in our Tsc2 +/− mice, as both are highly vascular lesions that contain a smooth muscle component and express elevated levels of the estrogen receptor and the HMB45 antigen ).…”

Survivin Expression in Tuberous Sclerosis Complex Cells

“…Their abnormal vasculature may lead to spontaneous life-threatening bleeding (4). Angiomyolipomas increase in size and/or number in about 60% of children affected by TSC, highlighting the need for close surveillance of the kidneys and the entire abdomen (5). TSC can occur in association with pulmonary lymphangioleiomyomatosis (LAM), a progressive and often fatal interstitial lung disease characterized by the diffuse proliferation of abnormal smooth muscle cells and cystic degeneration of lung parenchyma.…”