Nearly all patients with tuberous sclerosis complex (TSC) develop renal angiomyolipomas, although the tumor cell of origin is unknown. We observed decreased renal angiomyolipoma development in patients with TSC2- polycystic kidney disease 1 deletion syndrome and hypertension that were treated from an early age with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers compared with patients who did not receive this therapy. TSC-associated renal angiomyolipomas expressed ANG II type 1 receptors, platelet-derived growth factor receptor-β, desmin, α-smooth muscle actin, and VEGF receptor 2 but did not express the adipocyte marker S100 or the endothelial marker CD31. Sera of TSC patients exhibited increased vascular mural cell-secreted peptides, such as VEGF-A, VEGF-D, soluble VEGF receptor 2, and collagen type IV. These findings suggest that angiomyolipomas may arise from renal pericytes. ANG II treatment of angiomyolipoma cells in vitro resulted in an exaggerated intracellular Ca(2+) response and increased proliferation, which were blocked by the ANG II type 2 receptor antagonist valsartan. Blockade of ANG II signaling may have preventative therapeutic potential for angiomyolipomas.

Domoic acid (DA), an excitatory amino acid produced by diatoms belonging to the genus Pseudo-nitzschia, is a glutamate analog responsible for the neurologic condition referred to as amnesic shellfish poisoning. To date, the renal effects of DA have been underappreciated, although renal filtration is the primary route of systemic elimination and the kidney expresses ionotropic glutamate receptors. To characterize the renal effects of DA, we administered either a neurotoxic dose of DA or doses below the recognized limit of toxicity to adult Sv128/Black Swiss mice. DA preferentially accumulated in the kidney and elicited marked renal vascular and tubular damage consistent with acute tubular necrosis, apoptosis, and renal tubular cell desquamation, with toxic vacuolization and mitochondrial swelling as hallmarks of the cellular damage. Doses$0.1 mg/kg DA elevated the renal injury biomarkers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, and doses$0.005 mg/kg induced the early response genes c-fos and junb. Coadministration of DA with the broad spectrum excitatory amino acid antagonist kynurenic acid inhibited induction of c-fos, junb, and neutrophil gelatinase-associated lipocalin. These findings suggest that the kidney may be susceptible to excitotoxic agonists, and renal effects should be considered when examining glutamate receptor activation. Additionally, these results indicate that DA is a potent nephrotoxicant, and potential renal toxicity may require consideration when determining safe levels for human exposure.

The levels of galactose and galactitol in the sera of 6 young adults after ingestion of 0.25 g/kg of galactose alone or with the same quantity of glucose were studied. The results showed that: glucose decreased significantly the galactosemia and galactitolemia observed after ingestion of galactose alone; repeated consumption on 4 consecutive days of galactose alone induced an increase in galactosemia, and more significantly in galactitolemia. The addition of glucose to galactose in the same conditions abolished these effects.

Domoic acid (DA) is a glutamate analog and a characterized neurotoxicant. Outside of the CNS, glutamate receptors are also found in peripheral tissues, including the kidney, which opens the possibility that the kidney may also be susceptible to excitatory toxicity. When mice were injected with DA (2.5 mg/kg, i.p.), and euthanized between 30 min and 2 hr after injection, DA concentrations were approximately four‐fold higher in the kidney than any other tissue examined. Probenecid co‐administration (600 mg/kg) further augmented concentrations in the serum, kidney, heart and hippocampus, highlighting organic anion transporters in the renal clearance of DA. To determine nephrotoxicity, mice were injected with DA (0.25–2.5 mg/kg), a range below that which elicits overt neurotoxic effects, for three consecutive days. No change in serum creatinine was observed; however, urinary NGAL was elevated within 24 hr, and urinary kidney injury molecule‐1 (uKim‐1) was elevated 72 hr after initial dose. Tissue analysis also showed elevated NGAL and Kim‐1 protein in the kidneys of mice exposed to DA. Additionally, fluorescent imaging revealed alterations in aquaporin‐2 and Na+,K+‐ATPase localization in medullary collecting ducts. Finally, when DA was administered after a 12 hr dehydration period, uKim‐1 was increased compared to DA alone, suggesting water restriction exacerbated kidney injury. Overall the data indicate that DA is preferentially distributed to the kidneys, clearance is dependent upon organic anion transport, and renal toxicity occurs within a concentration range below what is known to elicit neurotoxicity. JAF is supported by the training grant 5T32DK007752–14 (NIDDK/NIH).