VEPTP inhibition with an extracellular domain targeting antibody did not restore albuminuria in a mouse model of diabetic kidney disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. DKD is a heterogeneous disease with complex pathophysiology where early endothelial dysfunction is associated with disease progression. The Tie2 receptor and Angiopoietin 1 and 2 ligands are critical for maintaining endothelial cell permeability and integrity.

Glucosylceramide synthase modulation ameliorates murine renal pathologies and promotes macrophage effector function in vitro.

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease.

Correction of cilia structure and function alleviates multi-organ pathology in Bardet-Biedl syndrome mice.

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2-/- cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS.

Glycosphingolipid metabolism and polycystic kidney disease.

Sphingolipids and glycosphingolipids are classes of structurally and functionally important lipids that regulate multiple cellular processes, including membrane organization, proliferation, cell cycle regulation, apoptosis, transport, migration, and inflammatory signalling pathways. Imbalances in sphingolipid levels or subcellular localization result in dysregulated cellular processes and lead to the development and progression of multiple disorders, including polycystic kidney disease. This review will describe metabolic pathways of glycosphingolipids with a focus on the evidence linking glycosphingolipid mediated regulation of cell signalling, lipid microdomains, cilia, and polycystic kidney disease.

Differences in the timing and magnitude of Pkd1 gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of ADPKD.

Development of a disease-modifying therapy to treat autosomal dominant polycystic kidney disease (ADPKD) requires well-characterized preclinical models that accurately reflect the pathology and biochemical changes associated with the disease. Using a Pkd1 conditional knockout mouse, we demonstrate that subtly altering the timing and extent of Pkd1 deletion can have a significant impact on the origin and severity of kidney cyst formation. Pkd1 deletion on postnatal day 1 or 2 results in cysts arising from both the cortical and medullary regions, whereas deletion on postnatal days 3-8 results in primarily medullary cyst formation.

CaMKII as a pathological mediator of ER stress, oxidative stress, and mitochondrial dysfunction in a murine model of nephronophthisis.

Polycystic kidney diseases (PKDs) are genetic diseases characterized by renal cyst formation with increased cell proliferation, apoptosis, and transition to a secretory phenotype at the expense of terminal differentiation. Despite recent progress in understanding PKD pathogenesis and the emergence of potential therapies, the key molecular mechanisms promoting cystogenesis are not well understood. Here, we demonstrate that mechanisms including endoplasmic reticulum stress, oxidative damage, and compromised mitochondrial function all contribute to nephronophthisis-associated PKD.

CDK inhibitors R-roscovitine and S-CR8 effectively block renal and hepatic cystogenesis in an orthologous model of ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) and other forms of PKD are associated with dysregulated cell cycle and proliferation. Although no effective therapy for the treatment of PKD is currently available, possible mechanism-based approaches are beginning to emerge. A therapeutic intervention targeting aberrant cilia-cell cycle connection using CDK-inhibitor R-roscovitine showed effective arrest of PKD in jck and cpk models that are not orthologous to human ADPKD.

Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease.

Genetic forms of polycystic kidney diseases (PKDs), including nephronophthisis, are characterized by formation of fluid-filled cysts in the kidneys and progression to end-stage renal disease. No therapies are currently available to treat cystic diseases, making it imperative to dissect molecular mechanisms in search of therapeutic targets. Accumulating evidence suggests a pathogenic role for glucosylceramide (GlcCer) in multiple forms of PKD.

mTOR signaling in polycystic kidney disease.

Polycystic kidney diseases (PKDs) comprise a large group of genetic disorders characterized by formation of cysts in the kidneys and other organs, ultimately leading to end-stage renal disease. Although PKDs can be caused by mutations in different genes, they converge on a set of common molecular mechanisms involved in cystogenesis and ciliary dysfunction, and can be qualified as ciliopathies. Recent advances in understanding the mechanisms regulating disease progression have led to the development of new therapies that are being tested in both preclinical and clinical trials.

Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models.

Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways.

Pkd1 and Nek8 mutations affect cell-cell adhesion and cilia in cysts formed in kidney organ cultures.

Development of novel therapies for polycystic kidney disease (PKD) requires assays that adequately reflect disease biology and are adaptable to high-throughput screening. Here we describe an embryonic cystic kidney organ culture model and demonstrate that a new mutant allele of the Pkd1 gene (Pkd1(tm1Bdgz)) modulates cystogenesis in this model. Cyst formation induced by cAMP is influenced by the dosage of the mutant allele: Pkd1(tm1Bdgz) -/- cultures develop a larger cystic area compared with +/+ counterparts, while Pkd1(tm1Bdgz) +/- cultures show an intermediate phenotype.

Hox/Pbx and Brn binding sites mediate Pax3 expression in vitro and in vivo.

Pax3 is a paired-homeodomain class transcription factor that serves a role in dorsal-ventral and medial-lateral patterning during vertebrate embryogenesis. Its expression is localized to dorsal domains within the developing neural tube and lateral domains within the developing somite. Additionally, modulation of its expression occurs along the rostral-caudal axis.

Wt1 functions in the development of germ cells in addition to somatic cell lineages of the testis.

The Wilms' tumor suppressor gene, Wt1, encodes a transcription factor critical for development of the urogenital system. To identify lineages within the developing urogenital system that have a cell-autonomous requirement for Wt1, chimeric mice were generated from Wt1-null ES cells. Males with large contributions of Wt1-/- cells showed hypoplastic and dysgenic testes, with seminiferous tubules lacking spermatogonia.

Role of the WT1 tumor suppressor in murine hematopoiesis.

The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal hematopoiesis is not well understood.

A mutant form of the Wilms' tumor suppressor gene WT1 observed in Denys-Drash syndrome interferes with glomerular capillary development.

The Wilms' tumor suppressor gene WT1 encodes a zinc finger protein that is required for urogenital development. In the kidney, WT1 is most highly expressed in glomerular epithelial cells or podocytes, which are an essential component of the filtering system. Human subjects heterozygous for point mutations in the WT1 gene develop renal failure because of the formation of scar tissue within glomeruli.

A mammal-specific exon of WT1 is not required for development or fertility.

The WT1 tumor suppressor gene is a zinc finger-containing transcription factor which is required for development of the kidney and gonads. A mammal-specific alternative splicing event within this gene results in the presence or absence of a 17-amino-acid sequence within the WT1 protein. To determine the function of this sequence in vivo, gene targeting was utilized to specifically eliminate the exon encoding this sequence in mice.