High-throughput screens for agonists of bone morphogenetic protein (BMP) signaling identify potent benzoxazole compounds.

Bone morphogenetic protein (BMP) signaling is critical in renal development and disease. In animal models of chronic kidney disease (CKD), re-activation of BMP signaling is reported to be protective by promoting renal repair and regeneration. Clinical use of recombinant BMPs, however, requires harmful doses to achieve efficacy and is costly because of BMPs' complex synthesis.

Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain.

The Pax gene family encodes DNA binding transcription factors that control critical steps in embryonic development and differentiation of specific cell lineages. Often, Pax proteins are re-expressed or ectopically expressed in cancer and other diseases of abnormal proliferation, making them attractive targets for tissue specific inhibition by small molecules. In this report, we used a homology model of the Pax2 paired domain and a virtual screen to identify small molecules that can inhibit binding of the paired domain to DNA and Pax2 mediated transcription activation.

The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice.

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and is increasing with the rising rate of obesity in the developed world. Signaling pathways known to influence the rate of lipid deposition in liver, known as hepatic steatosis, include the transforming growth factor (TGF) superfamily, which function through the SMAD second messengers. The kielin/chordin-like protein (KCP) is a large secreted protein that can enhance bone morphogenetic protein signaling while suppressing TGF-β signaling in cells and in genetically modified mice.

Evidence for intermediate mesoderm and kidney progenitor cell specification by Pax2 and PTIP dependent mechanisms.

Activation of the Pax2 gene marks the intermediate mesoderm shortly after gastrulation, as the mesoderm becomes compartmentalized into paraxial, intermediate, and lateral plate. Using an EGFP knock-in allele of Pax2 to identify and sort cells of the intermediate mesodermal lineage, we compared gene expression patterns in EGFP positive cells that were heterozygous or homozygous null for Pax2. Thus, we identified critical regulators of intermediate mesoderm and kidney development whose expression depended on Pax2 function.

Mechanisms of gene activation and repression by Pax proteins in the developing kidney.

During embryonic development, DNA binding proteins help specify and restrict the fates of pluripotent stem cells. In the developing kidney, Pax2 proteins are among the earliest markers for the renal epithelial cell lineage, with expression in the mesenchyme and in proliferating epithelia. The Pax2 protein is essential for interpreting inductive signals emanating from the ureteric bud such that the kidney mesenchyme can convert to epithelia.

Stem cells derived from neonatal mouse kidney generate functional proximal tubule-like cells and integrate into developing nephrons in vitro.

We have recently shown that kidney-derived stem cells (KSCs) isolated from the mouse newborn kidney differentiate into a range of kidney-specific cell types. However, the functionality and integration capacity of these mouse KSCs remain unknown. Therefore, the main objectives of this study were (1) to determine if proximal tubule-like cells, generated in vitro from KSCs, displayed absorptive function typical of proximal tubule cells in vivo, and (2) to establish whether the ability of KSCs to integrate into developing nephrons was comparable with that of metanephric mesenchyme (MM), a transient population of progenitor cells that gives rise to the nephrons during kidney organogenesis.

Differentiation of podocyte and proximal tubule-like cells from a mouse kidney-derived stem cell line.

In this study we have shown that the papilla of the mouse kidney contains a population of Pax2+ cells that are detectable from the early postnatal period through to adulthood. Lineage analysis suggests that some of these Pax2+ cells are derived from the metanephric mesenchyme, a population of progenitor cells that gives rise to the nephrons during kidney organogenesis. Here we describe a method for isolating and culturing the Pax2+ population, and demonstrate that some cells within this population are multipotent stem cells, as they are clonogenic and appear to undergo unlimited self-renewal.

The potential of small chemical functional groups for directing the differentiation of kidney stem cells.

In the future, stem-cell-based therapies could offer new approaches to treat kidney disease and reduce the incidence of ESRD (end-stage renal disease), but, as yet, research in this area is only being conducted in rodents and it is not clear whether or when it could be applied to human patients. Drug therapies, on the other hand, have been very effective at delaying the progression of kidney disease, but, for various reasons, current drug regimes are not suitable for all patients. A greater understanding of the molecular mechanisms that underlie disease progression in chronic kidney disease could help to identify novel drug targets.