The Sweet Pee model for Sglt2 mutation.

Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation. Here, we describe Sweet Pee, a mouse model that carries a nonsense mutation in the Slc5a2 gene, which results in the loss of sglt2 protein function. The phenotype of Sweet Pee mutants was remarkably similar to patients with mutations in the Scl5a2 gene. The Sweet Pee mutants had improved glucose tolerance, higher urinary excretion of calcium and magnesium, and growth retardation. Renal physiologic studies demonstrated a prominent distal osmotic diuresis without enhanced natriuresis. Sweet Pee mutants did not exhibit increased KIM-1 or NGAL, markers of acute tubular injury. After induction of diabetes, Sweet Pee mice had better overall glycemic control than wild-type control mice, but had a higher risk for infection and an increased mortality rate (70% in homozygous mutants versus 10% in controls at 20 weeks). In summary, the Sweet Pee model allows study of the long-term benefits and risks associated with inhibition of SGLT2 for the management of diabetes. Our model suggests that inhibiting SGLT2 may improve glucose control but may confer increased risks for infection, malnutrition, volume contraction, and mortality.

Mouse models to study kidney development, function and disease.

PURPOSE OF REVIEW: The mouse is the most widely used model organism to study gene function in the kidney in vivo. Here we review recent advances in technologies to manipulate the mouse genome and gene function to study renal biology. We discuss strengths and weaknesses of the approaches and provide examples in which they have been used to address renal questions. In addition, we provide a summary of the available resources of mouse tools and gene-targeting consortia. RECENT FINDINGS: Although conventional gene-targeting and spontaneous genetic mutations in mice have provided great insights into kidney function over several decades, the addition of powerful renal-specific gene-targeting tools and the advent of RNA technologies to manipulate gene function in vivo allow investigators to address research questions more precisely in the laboratory. Together with the establishment of multiple international consortia to target all the genes in the mouse genome and the development of gene trap and N-ethyl-N-nitrosourea resources, genetic manipulation in mice has become more efficient. SUMMARY: The availability of newer technologies and tremendous resources for mouse strains and reagents ensures that the mouse will remain a key model organism to study renal function.