Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney
Georgina Gyarmati, Urvi Nikhil Shroff, Anne Riquier-Brison, Dorinne Desposito, Wenjun Ju, Sean D. Stocker, Audrey Izuhara, Sachin Deepak, Alejandra Becerra Calderon, James L. Burford, Hiroyuki Kadoya, Ju-Young Moon, Yibu Chen, Markus M. Rinschen, Nariman Ahmadi, Lester Lau, Daniel Biemesderfer, Aaron W. James, Liliana Minichiello, Berislav V. Zlokovic, Inderbir S. Gill, Matthias Kretzler, János Peti-Peterdi
Georgina Gyarmati, Urvi Nikhil Shroff, Anne Riquier-Brison, Dorinne Desposito, Wenjun Ju, Sean D. Stocker, Audrey Izuhara, Sachin Deepak, Alejandra Becerra Calderon, James L. Burford, Hiroyuki Kadoya, Ju-Young Moon, Yibu Chen, Markus M. Rinschen, Nariman Ahmadi, Lester Lau, Daniel Biemesderfer, Aaron W. James, Liliana Minichiello, Berislav V. Zlokovic, Inderbir S. Gill, Matthias Kretzler, János Peti-Peterdi
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Research Article Nephrology

Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney

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 an existing remodeling capacity. This study uncovered endogenous tissue remodeling mechanisms in the kidney that were activated by the loss of body fluid and salt and regulated by a unique niche of a minority renal cell type called the macula densa (MD). Here, we identified neuronal differentiation features of MD cells that sense the local and systemic environment and secrete angiogenic, growth, and extracellular matrix remodeling factors, cytokines and chemokines, and control resident progenitor cells. Serial intravital imaging, MD nerve growth factor receptor and Wnt mouse models, and transcriptome analysis revealed cellular and molecular mechanisms of these MD functions. Human and therapeutic translation studies illustrated the clinical potential of MD factors, including CCN1, as a urinary biomarker and therapeutic target in chronic kidney disease. The concept that a neuronally differentiated key sensory and regulatory cell type responding to organ-specific physiological inputs controls local progenitors to remodel or repair tissues may be applicable to other organs and diverse tissue-regenerative therapeutic strategies.

Authors

Georgina Gyarmati, Urvi Nikhil Shroff, Anne Riquier-Brison, Dorinne Desposito, Wenjun Ju, Sean D. Stocker, Audrey Izuhara, Sachin Deepak, Alejandra Becerra Calderon, James L. Burford, Hiroyuki Kadoya, Ju-Young Moon, Yibu Chen, Markus M. Rinschen, Nariman Ahmadi, Lester Lau, Daniel Biemesderfer, Aaron W. James, Liliana Minichiello, Berislav V. Zlokovic, Inderbir S. Gill, Matthias Kretzler, János Peti-Peterdi

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Figure 6

The phenotype of MD-NGFR–KO mice.

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The phenotype of MD-NGFR–KO mice. (A) Increased frequency of MD cell Ca2...
(A) Increased frequency of MD cell Ca2+ transients in MD-NGFR–KO vs. WT mice. Single MD cell (left) and whole-MD recording (center, original/smoothed) of G5F transients in WT (green) and MD-NGFR–KO mice (red). GFR changes (normalized to baseline before induction/treatment) in WT treated with vehicle (control) or NGF and MD-NGFR–KO mice (right); n = 4–5. (B) Reduced MD cell connectivity and sensitivity in MD-NGFR–KO vs. WT mice. Left: Functional MD cell–to-cell connectivity map of all 21 (WT) and 18 (MD-NGFR–KO) individually numbered MD cells. Red line connecting individual cell pairs indicates Pearson’s r > 0.35. Red and blue cell color indicates hub and lone cells, respectively. Center: Heatmap of each MD cell pair’s Pearson’s coefficient in 2-color gradient, as in scale. Right: Effect of i.v. gastrin on MD cell Ca2+ (G5F) in WT vs. MD-NGFR–KO mice; n = 4–8 (average of 4–5 MD cells/animal). (C–E) Renin cell density (C), endothelial injury and podocyte number (D), and renal pathology (E) in WT mice treated with vehicle (control) or NGF,and MD-NGFR–KO mice. n = 4–5 (average of 5 glomeruli/animal). Renin, PLVAP, KIM1 immunofluorescence (red) images and PAS-stained kidney tissue sections, and summary of respective cell numbers, labeling density (tissue fibrosis index), and albuminuria (ACR). Cell nuclei are labeled blue with DAPI, tissue autofluorescence (C, green) is shown for tissue morphology. Scale bar: 50 μm (C–E). (F) Representative immunoblots and summary of MD-specific protein expression in renal cortical homogenates, including CCN1, CCN3, and CXCL14 in WT vs. MD-NGFR–KO mice; n = 4. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 using Student’s t test (B and D–F) or ANOVA followed by Dunnett’s test (A and C).