A recent study led by USC Stem Cell scientist Janos Peti-Peterdi reveals that a loss of salt and body fluid can stimulate kidney regeneration and repair in mice. This groundbreaking research, published in the Journal of Clinical Investigation, uncovers an innate regenerative response driven by a small population of kidney cells known as the macula densa (MD). These cells play a crucial role in sensing salt and controlling filtration, hormone secretion, and other vital kidney functions.
Peti-Peterdi, a professor of physiology, neuroscience, and medicine at the Keck School of Medicine of USC, emphasizes the importance of this discovery in the fight against kidney disease, which affects one in seven adults worldwide. “Our mission is to find a cure for kidney disease, a growing global epidemic affecting 850 million people worldwide,” he said. “Currently, there is no cure for this silent disease, and by the time it is diagnosed, the kidneys are irreversibly damaged.”
To tackle this issue, Peti-Peterdi and his team adopted a unique approach. Instead of examining why diseased kidneys fail to regenerate, they investigated how healthy kidneys evolved. “From an evolutionary biology perspective, the primitive kidney structure of fish evolved into more complex and efficient kidneys in birds and mammals,” Peti-Peterdi explained. “This adaptation was necessary for survival in a dry land environment, and these are the mechanisms we aim to mimic in our research.”
The researchers fed lab mice a very low salt diet and administered an ACE inhibitor to further reduce salt and fluid levels. This regimen, followed for up to two weeks, led to regenerative activity in the MD region, which could be blocked by drugs interfering with MD signals. This finding highlighted the MD's crucial role in orchestrating kidney regeneration.
Further analysis revealed that MD cells share genetic and structural similarities with nerve cells, which are known to regulate regeneration in other organs. The scientists identified specific signals from genes such as Wnt, NGFR, and CCN1 that were enhanced by a low-salt diet, promoting kidney regeneration. Notably, CCN1 activity was significantly reduced in patients with chronic kidney disease (CKD).
To explore therapeutic applications, the team administered CCN1 to mice with focal segmental glomerulosclerosis, a type of CKD. They also treated these mice with MD cells grown in low-salt conditions. Both treatments successfully improved kidney structure and function, with MD cell treatment showing the most significant benefits. This success might be attributed to MD cells secreting not only CCN1 but also other unknown factors that promote regeneration.
“We believe in the importance of this new perspective on kidney repair and regeneration,” Peti-Peterdi stated. “We are confident that this approach will lead to a powerful new therapeutic strategy.”
This study represents a significant step forward in understanding kidney regeneration and offers hope for developing effective treatments for kidney disease in the near future.
Source: University of Southern California