Arginine reprogramming in ADPKD results in arginine-dependent cystogenesis.

Research into metabolic reprogramming in cancer has become commonplace, yet this area of research has only recently come of age in nephrology. In light of the parallels between cancer and autosomal dominant polycystic kidney disease (ADPKD), the latter is currently being studied as a metabolic disease. In clear cell renal cell carcinoma (RCC), which is now considered a metabolic disease, we and others have shown derangements in the enzyme arginosuccinate synthase 1 (ASS1), resulting in RCC cells becoming auxotrophic for arginine and leading to a new therapeutic paradigm involving reducing extracellular arginine.

Anticystogenic activity of a small molecule PAK4 inhibitor may be a novel treatment for autosomal dominant polycystic kidney disease.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a common hereditary renal disease with no currently available targeted therapies. Based on the established connection between β-catenin signaling and renal ciliopathies, and on data from our and other laboratories showing striking similarities of this disease and cancer, we evaluated the use of an orally bioavailable small molecule, KPT-9274 (a dual inhibitor of the protein kinase PAK4 and nicotinamide phosphoribosyl transferase), for treatment of ADPKD. Treatment of PKD-derived cells with this compound not only reduces PAK4 steady-state protein levels and regulates β-catenin signaling, but also inhibits nicotinamide phosphoribosyl transferase, the rate-limiting enzyme in a key NAD salvage pathway.

The cpk model of recessive PKD shows glutamine dependence associated with the production of the oncometabolite 2-hydroxyglutarate.

Since polycystic kidney disease (PKD) was first noted over 30 years ago to have neoplastic parallels, there has been a resurgent interest in elucidating neoplasia-relevant pathways in PKD. Taking a nontargeted metabolomics approach in the B6(Cg)-Cys1(cpk/)J (cpk) mouse model of recessive PKD, we have now characterized metabolic reprogramming in these tissues, leading to a glutamine-dependent TCA cycle shunt toward total 2-hydroxyglutarate (2-HG) production in cpk compared with B6 wild-type kidney tissue. After confirmation of increased 2-HG expression in immortalized collecting duct cpk cells as well as in human autosomal recessive PKD tissue using targeted analysis, we show that the increase in 2-HG is likely due to glutamine-sourced α-ketoglutarate.

Biomarkers in IgA nephropathy.

IgA nephropathy is the most common primary glomerulonephritis and presents with gross hematuria and upper respiratory infection, with slow progression to end-stage renal disease in up to 50% of affected patients. Kidney biopsies are the gold standard method of diagnosis and frequently are not performed as the majority of individuals are asymptomatic. Thus, there is a need to discover and validate prognostic and predictive biomarkers that can be noninvasively obtained and are specific to this disease.

Mapping the deletion endpoints in individuals with 22q11.2 deletion syndrome by droplet digital PCR.

Background: Chromosome 22q11.2 deletion syndrome (22q11DS) is the most common human microdeletion syndrome and is associated with many cognitive, neurological and psychiatric disorders. The majority of individuals have a 3 Mb deletion while others have a nested 1.

Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.

Deletion of the 1.5-3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.