The podocyte has emerged as the focus of intense investigation for kidney researchers. This cell is located at the key transition point in the glomerulus where the plasma is filtered through the basement membrane to enter the urinary space to begin the journey to become urine. Over the last 10 years, mutations in multiple genes important to podocyte function have been linked to altered podocyte health and ultimately progressive kidney disease, such as focal segmental glomerulosclerosis among others. It has been thought that the podocyte is terminally differentiated, and multiple kidney diseases associated with proteinuria, such as diabetic nephropathy, have been shown to have decreased podocyte number per glomeruli and increased podocyte shedding in the urine (podocyturia). Interestingly, podocyturia or reduced podocyte turnover has been described in healthy individuals. Thus, the mechanisms governing podoctye loss, repopulation, and the process of shedding these cells in the urine are still being defined and could represent a key pathologic process in kidney disease. In a recent Research Letter to AJKD, by Maestoni et al helps to further characterize podocytes shed in the urine of healthy individuals. The study phenotypically characterized the podocytes found in the urine of 20 healthy controls and the kidneys of 15 adults (derived from kidneys removed for renal or urothelial carcinoma or from donor kidneys not suitable for transplantation). They demonstrate that these podocytes have markers suggestive of dedifferentiation. They first demonstrated that podocytes from the urine (they estimated ~300 are shed per day) contained mRNA for both markers of both podocytes (podocin, nephin and podocalyxin) and ongoing dedifferentiation (nanog, oct3/4, and sox2). This was surprising as it suggest that this terminally differentiated cell actually undergoes dedifferentiation. After these shed podocytes were placed into culture medium, they began to cluster and express nanog and podocalyxin (Podx1) by immunofluorescence. How do these cells arrive in the urine? Do they dedifferentiate in the kidney and then detach, or do they fall from the glomerulus and dedifferentiate after being shed? In order to address this, the authors examined the glomeruli of donor kidneys for dedifferentiated podocytes. Remarkably, they found discreet pockets of podocytes that stained for nanog, oct3/4, and sox2, suggesting that podocytes first dedifferentiate and are then shed into the urine. Also, lineage tracing of mature podocytes in mouse models could help to further define this process. In conclusion, these are provocative results that demonstrate and characterize podocyte turnover in healthy individuals. Understanding the molecular mechanism for how these cells are renewed and lost could help in treating a variety of kidney disorders.
Dr. Matt Sparks AJKD Blog Advisory Board member