Gene Expression in the Black Bear Kidney: A first Step Towards Understanding Recovery in Mammalian Kidneys
The inability of the human kidney to recover from damage leads to an ever-growing population of patients with chronic kidney disease that is dependent on dialysis, with over 50% of patients due to diabetic nephropathy. The broad goal of this study is to identify genetic and biological mechanisms that could mediate nephron recovery, thereby enabling patients to avoid dialysis. Evidence strongly suggests that kidney recovery takes place in the American black bear, providing a potentially powerful and previously unexplored platform for identifying genes and biological pathways that could regulate kidney recovery in mammals, including humans. The American black bear becomes hyperinsulinemic and develops characteristics of insulin resistance in the fall, and during hibernation its renal function drops to a level comparable to a dialysis patient. Furthermore, glomerulosclerosis, a hallmark of diabetic nephropathy, has been reported in bears shortly after hibernation. Yet, bears seem to recover within a short period of time after emerging from hibernation in the spring, and do this year after year. However, little is known of the process of kidney recovery in the black bear, including the time period of recovery and the genes and biological pathways involved. In this pilot study we will carry out the following Specific Aims: 1) determine a histological timeline of nephron recovery in the black bear by collecting samples during the spring and fall, and 2) identify genes that are differentially expressed in black bear kidneys as a function of nephron recovery through high-throughput sequencing of kidney RNA. We have already set up a network with Maine guides and bear biologists from Maine Native American tribes for collecting kidney samples by bear hunters and have already collected 38 samples during the 2014 spring hunting season. In addition, to enable gene expression analysis, we have completely sequenced the black bear genome. We expect to determine a reliable window during which nephron recovery in the black bear takes place and identify a set of genes that shows an expression pattern that follows the nephron recovery timeline. Results of these studies will be the first insights into mammalian nephron recovery. They will establish the foundation of future projects in which we will study the identified genes in mouse models of diabetic nephropathy to understand their normal role and whether manipulation of these genes or the molecular pathways in which they play a role, will lead to recovery. Future work will translate the results into human clinical studies.

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