Macula densa cells: a new target for kidney regeneration
A recent study has uncovered how mechanisms in the kidney, activated by low salt and body fluid, could offer a new avenue for kidney regeneration.
Researchers from the Keck School of Medicine of the University of Southern California (CA, USA) have explored the evolutionary and physiological adaptive responses of the kidney to improve our understanding of endogenous kidney tissue repair. They identify potential therapeutic targets that may aid the development of mechanism-based regenerative therapies for kidney disease regression.
The kidney is one of several organs in the human body with limited tissue regeneration capabilities. Chronic kidney disease (CKD), a global health issue affecting approximately one in every seven adults, is characterized by progressive damage to the kidneys and the depletion of their functionality. Conventional treatments like dialysis or transplantation are the current standards of care for CKD but, as dialysis requires frequent administration and the availability and compatibility of organs for transplant can present challenges, there is a need for more effective therapies.
In order to explore a new avenue for potential treatments, Janos Peti-Peterdi, Georgina Gyarmati and their team took an unusual approach, examining the evolutionary history of kidneys, focusing on the increase in their ability to sense and absorb more salt and water as animal life forms emerged from the sea and took to the land and skies.
Their experiments utilized Ng2-tdTomato and Cdh5-Confetti mouse models to genetically label and track mesenchymal and endothelial cell lineages, respectively, within the kidney cortex. These mouse models were administered a low-salt diet in conjunction with an angiotensin-converting enzyme inhibitor known as enalapril, a commonly prescribed drug that further lowered salt and fluid levels.
Under these low salt conditions, the researchers observed regenerative activity in macula densa (MD) cells, a small group of kidney cells in the distal tubule that sense salt and body fluid changes. In the Ng2-tdTomato mice, they observed significant recruitment of mesenchymal precursor cells that underwent differentiation into multiple cell types and observed significant recruitment of endothelial precursor cells in the Cdh5-Confetti mice that produced clonal remodeling of key structures.
Further investigation of the MD cells revealed that they exhibit characteristics similar to neurons and express neuronal enzymes like nitric oxide synthase 1 (NOS1). Additionally, in the MD cells of the mouse models, they identified the expression of Wnt, NGFR, and CCN1 genes, which can be enhanced by a low-salt diet to regenerate kidney structure and function. Notably, in patients with CKD, the activity of CCN1, an angiogenic factor, was found to be significantly decreased, making it a promising potential biomarker and therapeutical target.
To test the therapeutic potential of these discoveries, the researchers administered CCN1 protein to one cohort of mice with segmental glomerulosclerosis, a type of CKD, and MD cells grown in low-salt conditions to another. While both were successful, the MD cell treatment demonstrated the most significant improvement in kidney structure and function, possibly due to MD cells secreting CCN1 in addition to other factors that promote kidney regeneration.
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These findings highlight the intricate sensory and regulatory roles of MD cells within the nephron, including the role they play in kidney regeneration, likely triggered, as the researchers hypothesize, in response to low-salt conditions.
“We feel very strongly about the importance of this new way of thinking about kidney repair and regeneration,” expressed Peti-Peterdi. “And we are fully convinced that this will hopefully end up soon in a very powerful and new therapeutic approach.”
Looking ahead, the researchers plan to investigate whether targeting MD factors could lead to more effective therapeutic applications compared to current treatments for kidney diseases. This is especially important given the risks associated with persistent overactivation of the MD, which might result in pathogenic outcomes as observed in conditions like early diabetes.