Kidney protein could expand the window for developmental nephron production

A study in mice showed that a partial reduction of the protein hamartin in the developing kidney leads to larger numbers of nephrons. Nephrons—the basic functional unit of the kidney—consist of various cells and structures that work together to filter waste products and excess fluid from the blood. The final number of nephrons in the kidney is widely variable, but research has shown that higher numbers of nephrons correlate with improved kidney function, and that nephron loss occurs with aging. While this variability is not completely understood, several factors, such as premature birth, lead to low nephron numbers. In mammals, the production of nephrons in the kidney begins during prenatal development and ends before birth (e.g., in humans) or shortly thereafter (e.g., in mice), at which point the body cannot generate additional nephrons. Therefore, understanding the mechanisms that govern nephron generation during early development has the potential to inform strategies to increase nephron numbers in those at risk, thereby reducing the likelihood of kidney disease later in life.

Previous research demonstrated that a pool of kidney stem cells, called nephron progenitor cells (NPCs), can turn into nephrons when signaled to do so at just the right time during kidney development. A team of scientists discovered that a protein called Mtor seemed to be one of these important signals, and thus used genetic mouse models to investigate the role of Mtor—as well as its functional inhibitor, hamartin—in shaping the number of nephrons in the kidney. Mice engineered to completely lack either Mtor or hamartin in their NPCs did not survive beyond 2 days after birth because they were unable to develop functional kidneys. However, mice engineered to lack just one of the two gene copies encoding Mtor (effectively reducing Mtor levels by half) in NPCs survived but had significantly lower numbers of nephrons and smaller kidneys than their control counterparts. Conversely, genetic deletion of one copy of the gene encoding hamartin led to a greater number of nephrons than in control mice. Further analysis of the mice with a partial reduction in hamartin revealed that the developmental “window” for generating nephrons in the kidney extended by about 1 extra day, resulting in the significant increase in nephron number that was observed. Surprisingly, by combining these modified genetic backgrounds in mice, the scientists determined that the higher nephron number observed in mice with reduced hamartin was independent of the Mtor pathway. These findings define hamartin as part of an important pathway in mice that determines nephron number by regulating the window of time in which nephrons can form. Additionally, hamartin is coded by the gene Tsc1, which is involved in the development of a rare, multi-system genetic disease called tuberous sclerosis complex that causes benign tumors to grow in the kidney and other organs. Thus, future research building on these findings may shed light on cellular pathways in tuberous sclerosis complex, and, if the connection between numbers of nephrons and hamartin is conserved in humans, the hamartin signaling pathway could represent an important therapeutic target for people with or at risk for kidney disease.

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