A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746

25 Years In A Stereology Laboratory: A Point By Point History

In many experimental situations there is some three dimensional particle that is of interest to the microscopist. To obtain morphometric information about the particle, the microscopist must section some reference space that contains the particle or component of interest, but after sectioning, the reference space and component are reduced to a 2-D sample. This sample no longer contains 3-D structures but only 2-D profiles of the reference space and component.Stereology can be used to obtain 3-D information from 2-D samples. These samples can be micrographs or digital images, or they can even be the cut surface of the 3-D reference space. The four most basic parameters measured using stereological techniques are volume (3-D), area (2-D), length (1-D), and number (0-D). When measuring these parameters it is often advisable to first measure the density of the component within the reference space, next measure the volume of the reference space, and finally multiply the density by the reference volume to obtain the actual structural parameter.</jats:p

Early chronic low-level lead exposure produces glomerular hypertrophy in young C57BL/6J mice

AbstractEarly chronic lead exposure continues to pose serious health risks for children, particularly those living in lower socioeconomic environments. This study examined effects on developing glomeruli in young C57BL/6J mice exposed to low (30ppm), higher (330ppm) or no lead via dams’ drinking water from birth to sacrifice on post-natal day 28. Low-level lead exposed mice [BLL mean (SD); 3.19 (0.70)μg/dL] had an increase in glomerular volume but no change in podocyte number compared to control mice [0.03 (0.01)μg/dL]. Higher-level lead exposed mice [14.68 (2.74)μg/dL] had no change in either glomerular volume or podocyte number. The increase in glomerular volume was explained by increases in glomerular capillary and mesangial volumes with no change in podocyte volume. Early chronic lead exposure yielding very low blood lead levels alters glomerular development in pre-adolescent animals