Kidney function is essential for removing the wastes that result from normal cell function and maintaining water and salt balance in our internal tissues. These actions are carried out by roughly a million nephrons within the kidney that filter all the body’s blood roughly once every 1·2 hours. The kidney also regulates other tissues controlling blood pressure and blood cell composition, and regulating the strength of bone by activating vitamin D. Chronic kidney injury over time results in a loss of normal kidney function leading to end stage renal disease (ESRD). ESRD affects 500,000 Americans and its prevalence is increasing with a rise in diabetes and hypertension. ESRD is associated with significant morbidity and mortality: ultimately kidney transplant is the only cure but for every four patients requiring a transplant there are only enough available kidneys to help one. Life-threatening kidney injury also occurs through acute damage particularly in hospital settings were infection, toxic drugs or ischemia during surgery kills cells in the nephron shutting down the kidneys. Animal studies indicate that the kidney is unable to make new nephrons: the nephron complement is established prior to birth. However, the damaged nephron has a limited capacity to restore activity through the regeneration of missing cells by their surviving neighbors.
Our research has focused on an understanding of the progenitor cell types that build the kidney and the damage repair processes that restore function following an acute kidney. While there is a considerable understanding of nephron progenitors in the mouse, our understanding of their human counter parts is limited. We have examined human nephron progenitors and identified differences in the regulatory factors responsible for regulating the nephron progenitor state. Recent progress has enabled kidney-like structures, kidney organoids, to develop in cell culture from pluripotent stem cells. This advance will facilitate the characterization of human kidney progenitors and the structures to which they give rise. To take advantage of these systems we have developed genetically modified cell lines where activation of a fluorescent marker signals the formation of kidney cell types of interest in kidney organoid cultures. With these, we can optimize protocols for nephron generation in the dish and determine if key cell types mirror the molecular properties of their counterparts in the normal kidney.
In kidney repair, we have identified a regulatory factor, SOX9, activated on kidney injury in cells that go onto repair kidney tubule damage. Further, SOX9 action is critical for the normal repair process. Understanding how SOX9 operates in renal repair may provide means to activate and augment repair processes to effect lasting repair following kidney damage. This is particularly important not only because of the high mortality (more than 40%) associated with acute kidney injury, but the increased likelihood that a patient that survives acute injury succumbs to chronic disease often times many years after the injurious event.
To provide additional insight into both the repair process and the transition over time to chronic kidney disease, we have generated a BioBank resource of injured and repairing kidney samples and characterized these extensively at the molecular level. This resource forms the basis for both hypothesis driven research of ideas emerging from these data sets and an information set to be correlated to events at play in the human kidney to focus future studies on the most human-relevant components of the mouse kidneys injury and repair responses. Our CIRM leadership award is moving from discovery to functional analysis with the ultimate goals of clinical translation