Kidney mass increases or adapts to growing body mass by the time we achieve early adulthood. When the body loses one kidney—from trauma, injury or donating a kidney—the remaining kidney also enlarges to maintain the requirements for glomerular filtration. These changes in kidney size are the result of renal hypertrophy.
Eric G. Neilson, MD, vice president for Medical Affairs and Lewis Landsberg Dean, coauthored a new paper, published recently in the Journal of Clinical Investigation, which reveals the biochemical mechanisms underlying kidney hypertrophy.
Hypertrophy happens when the cells in an organ individually increase their size. The new study demonstrates that pathways involving the mTOR complex activate both modes of kidney enlargement. However, unique molecular signaling of that pathway depends on context.
Through a series of complex experiments, the authors showed during normal maturation that receptor tyrosine kinases on proximal tubular cells activate class I PI3K/PTEN to regulate an MTORC1/lysosomal effect on protein synthesis leading to adaptive hypertrophy.
Alternatively, after the loss of a kidney, blood flow to the remaining kidney increases, delivering more amino acids to the organ than before. This amino acid load activates class III PI3K enzymes and vesicular trafficking to lysosomes that also activates MTORC1. The class III PI3K pathway likely explains why kidneys grow bigger when people consume high-protein diets or develop diabetes.
“We now have good answers for century-old questions,” said Dr. Neilson, who started the research when he was chairman of Medicine at Vanderbilt University School of Medicine. “The answers are important because the precise biochemical signaling for renal hypertrophy has been uncertain and because that signaling can trigger or accelerate chronic kidney diseases. Knowing the different molecular pathways for hypertrophy also potentially offers new drugable targets that may be helpful someday for patients who are at risk for unwanted hypertrophy.”
Dr. Neilson collaborated with scientists from Vanderbilt, the Medical College of Georgia at Georgia Regents University and Texas A&M University on this work.
“The same common mechanism—activation of the mTOR complex—leads to hypertrophy, but how you get there is different for normal adaptation of kidney size or for the remarkable compensatory growth after loss of one kidney,” said coauthor Raymond Harris, MD, chief of Nephrology and Hypertension at Vanderbilt.
The work was supported by National Institutes of Health (NIH) grants DK83575, DK38226, DK51265 and DK46282; American Heart Association Scientist Development Grant 0630274N; start-up funds from Georgia Regents University Augusta; a VA Merit Award; the Mochida Memorial Foundation for Medical and Pharmaceutical Research; the Uehara Memorial Foundation; and Grant-in-Aid for Research Activity Start-up from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
