Physiological activation of the nephron central command drives endogenous kidney tissue regeneration

Abstract

Tissue regeneration is limited in several organs including the kidney, contributing to the high prevalence of kidney disease globally. However, evolutionary and physiological adaptive responses and the presence of renal progenitor cells suggest existing remodeling capacity. This study uncovered a novel endogenous tissue remodeling mechanism in the kidney that is activated by the loss of body fluid and salt and involves a unique niche of chief cells called macula densa (MD) that control resident progenitor cells via secreted angiogenic, growth and extracellular matrix remodeling factors, cytokines and chemokines. Serial intravital imaging, MD Wnt mouse models and transcriptome analysis provide functional and molecular characterization of this newly identified MD program for kidney regeneration complemented with human and therapeutic translation. The concept that chief cells responding to organ-specific physiological inputs control local progenitors and direct them to remodel or repair tissues may be applicable to other organs and diverse tissue regenerative therapeutic strategies.

SGLT2 inhibition promotes glomerular repopulation by cells of renin lineage in experimental kidney disease

“…It would be of great interest to see the effect of such duplex treatment on CoRL‐mediated renal repair. As several macula densa‐mediated mechanisms involving, e.g., nNOS, COX‐2 and Wnt signaling are shared with other (progenitor) cells and tissue types during development and repair, macula densa cells, considered as chief cells of tubuloglomerular feedback, now also have been suggested to be the nephron's central command driving endogenous tissue remodeling under influence of organ‐specific physiological signals like body‐fluid and salt levels by others 36 . As such, these macula densa cells may be the key drivers of CoRL‐mediated regeneration.…”

“…As several macula densa-mediated mechanisms involving, e.g., nNOS, COX-2 and Wnt signaling are shared with other (progenitor) cells and tissue types during development and repair, macula densa cells, considered as chief cells of tubuloglomerular feedback, now also have been suggested to be the nephron's central command driving endogenous tissue remodeling under influence of organ-specific physiological signals like body-fluid and salt levels by others. 36 As such, these macula densa cells may be the key drivers of CoRL-mediated regeneration. Meanwhile, it has been argued that SGLT2 inhibitory treatment is not able to affect tubuloglomerular feedback in advanced CKD, but rather acts on pleiotropic mechanisms like local metabolism and favorable effects on vascular function.…”