Tuberous Sclerosis and Bilateral Renal Angiomyolipomas: A Case Report and Literature Review of Emerging Treatment Strategies.

Tuberous sclerosis complex is a rare multisystemic genetic disorder associated with the development of benign hamartomas. Angiomyolipomas are one such characteristic finding that may be seen in 55-80% of tuberous sclerosis complex patients. While being normally asymptomatic, they can also cause significant morbidity and mortality. We present the case of a patient with tuberous sclerosis complex and recently discovered bilateral renal angiomyolipomas, admitted for hematuria who underwent left renal artery embolization; however, worsening renal function necessitated subsequent nephrectomy. Despite still being mainstays of treatment, invasive interventions are now being recommended for specific patient populations as demonstrated in our case. Emerging strategies targeting the PI3K/AKT/mTOR pathway have been shown to reduce the size of angiomyolipomas and are now used to treat asymptomatic cases >3 cm. Our review discusses these treatment options with the intention of increasing awareness of current recommendations and hopefully leading to increased application of these novel therapies that will reduce the need for invasive interventions.

Acute Kidney Injury due to Crescentic Glomerulonephritis in a Patient with Polycystic Kidney Disease.

Polycystic kidney disease is an inherited condition, characterized by the development of cysts in the kidney, as well as in other organs. Patients with polycystic kidney can suffer from the same causes of acute kidney injury as the general population. Nephritic syndrome is an uncommon cause of acute kidney injury in the general population and less common in patients with polycystic kidney disease. We report the second case of crescentic glomerulonephritis, causing acute kidney injury, in a patient with polycystic kidney disease.

GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy.

Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor ß (TGF-ß), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-ß1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

Homocysteine-induced macrophage inflammatory protein-2 production by glomerular mesangial cells is mediated by PI3 Kinase and p38 MAPK.

BACKGROUND: Homocysteine (Hcy) and inflammatory cytokines have been linked to adverse outcomes in persons with cardiovascular and kidney diseases and recent reports suggest that cytokine-mediated inflammatory infiltrates may be an important contributor to the pathogenesis the aforementioned diseases. Although some reports suggest that Hcy directly influences inflammatory cytokine production, this proposition has not been supported by data from other studies. The objective of the current study was to a) utilize an in vitro cellular model to identify cytokines that may be affected by Hcy and b) examine the role of mitogen activated protein kinase (MAPK) and phosphatidyl inositol 3- (PI3) Kinase in Hcy modulated cytokine production. METHODS: Primary rat glomerular mesangial cells (MC, passage 8 to 15), isolated by standard sieving methodology, were exposed to Hcy (15, 50 or 100 muM) with L-cysteine (L-Cys; 100 muM) serving as a control. An antibody array was used to identify cytokines that were modulated when MCs were exposed to Hcy. Gene expression was assessed by quantitative RT-PCR, while western blotting analysis was used to assess cellular protein levels in the presence and absence of inhibitors of MAPK and PI3 Kinase. Finally, leukocyte adhesion assay was used to examine the effect of Hcy on leukocyte adhesion to glomerular MCs that were maintained in media without, and with, kinase inhibitors. RESULTS: We identified macrophage inflammatory protein 2 (MIP-2) as a key cytokine that manifested increases in both protein and mRNA following exposure of glomerular MC to pathophysiologic Hcy levels (50 muM). Further analyses revealed that Hcy-induced MIP-2 was dependent on activation of p38 MAPK and PI3 kinase. MIP-2 enhanced leukocyte adhesion to MC and this MIP-2-enhanced leukocyte adhesion was also dependent on activation of p38 MAPK and PI3K. Finally, we demonstrate that leukocyte adhesion to MC is specifically inhibited by anit-MIP2 antibody. CONCLUSION: The data suggest that Hcy participates in inflammatory cytokines production by glomerular MC and that Hcy-induced MIP-2 mediates leukocyte adhesion to MC.

Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease.

Mutations in PKHD1 cause autosomal recessive polycystic kidney disease (ARPKD). We produced a mouse model of ARPKD by replacing exons 1-3 of Pkhd1 with a lacZ reporter gene utilizing homologous recombination. This approach yielded heterozygous Pkhd1 (lacZ/+) mice, that expressed beta-galactosidase in tissues where Pkhd1 is normally expressed, and homozygous Pkhd1 (lacZ/lacZ) knockout mice. Heterozygous Pkhd1 (lacZ/+) mice expressed beta-galactosidase in the kidney, liver, and pancreas. Homozygous Pkhd1 (lacZ/lacZ) mice lacked Pkhd1 expression and developed progressive renal cystic disease involving the proximal tubules, collecting ducts, and glomeruli. In the liver, inactivation of Pkhd1 resulted in dilatation of the bile ducts and periportal fibrosis. Dilatation of pancreatic exocrine ducts was uniformly seen in Pkhd1 (lacZ/lacZ ) mice, with pancreatic cysts arising less frequently. The expression of beta-galactosidase, Pkd1, and Pkd2 was reduced in the kidneys of Pkhd1 (lacZ/lacZ ) mice compared with wild-type littermates, but no changes in blood urea nitrogen (BUN) or liver function tests were observed. Collectively, these results indicate that deletion of exons 1-3 leads to loss of Pkhd1 expression and results in kidney cysts, pancreatic cysts, and biliary ductal plate malformations. The Pkhd1 (lacZ/lacZ ) mouse represents a new orthologous animal model for studying the pathogenesis of kidney cysts and biliary dysgenesis that characterize human ARPKD.

Lifelong genetic minipumps.

Most physiologists working with animals are familiar with osmotic minipumps. These surgically implanted devices can, for a limited period, administer a reagent at a constant predetermined rate that is unaffected by concurrent procedures. The investigator can then test the physiological effects of other treatments knowing that the animals' homeostatic responses will not be able to alter the dose of the pumped reagent. To develop the genetic equivalent of a lifelong minipump, simply inherited as an autosomal dominant, we here combine three of our previously described strategies, genetic clamping, single-copy chosen-site integration, and modification of untranslated regions (UTRs). As a test of the procedure, we have generated a series of intrinsically useful animals having genetic minipumps secreting renin ectopically from the liver at levels controlled by the investigator but not subject to homeostatic changes. To achieve the different dosage levels of these genetic minipumps, we altered the UTRs of a renin transgene driven by an albumin promoter and inserted it into the genome as a single copy at the ApoA1/ApoC3 locus, a locus that is strongly expressed in the liver. The resulting mice express plasma renin over ranges from near physiological to eightfold wild type and develop graded cardiovascular and kidney disease consequent to their different levels of ectopically secreted renin. The procedure and DNA constructs we describe can be used to generate genetic minipumps for controlling plasma levels of a wide variety of secreted protein products.