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Abstract: PO1720

Pacemaker Macula Densa Cells Form a Nephron-Level Autonomous Somatosensory Neuronal Network

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Gyarmati, Georgina, University of Southern California, Los Angeles, California, United States
  • Riquier-brison, Anne, University of Southern California, Los Angeles, California, United States
  • Shroff, Urvi Nikhil, University of Southern California, Los Angeles, California, United States
  • Peti-Peterdi, Janos, University of Southern California, Los Angeles, California, United States
Background

The autonomous nervous system in several organs performs local control of organ functions. Macula densa (MD) cells that are specialized renal epithelial cells capable of sensing the local tissue environment and releasing various chemical messengers to control nearby cells have well-known neuronal features. This study addressed the hypothesis that MD cells perform neuron-like functions that play important roles in maintaining key organ functions.

Methods

MD-GT mice with MD-specific inducible expression of the Ca2+ sensitive fluorescence reporter GCaMP5 and the calcium insensitive tdTomato were developed to visualize the Ca2+ homeostasis of MD cells with multiphoton microscopy (MPM). Whole transcriptome RNA seq was performed to establish the gene profile of MD cells providing molecular detail of their function.

Results

MD cell imaging in vivo revealed regularly oscillating, propagating Ca2+-firing pacemaker activity with peaks showing ~4-fold elevations and average frequency of 0.03/s. This phenomenon was preserved in freshly isolated MD-GT cells in vitro indicating autonomous pacemaker function. Several divergent stimuli altered steady-state Ca2+ and/or firing frequency, including mechanical (tubule flow), altered tubular fluid composition (low salt diet), local autacoids (angiotensin II), systemic hormones (AVP, CaSR mimetic), and metabolic states (diabetic hyperglycemia). Bolus injection of the β-agonist Isoproterenol caused the most robust changes in firing frequency as compared to control (frequency fold change 3.4±0.6 and 0.9±0.1, respectively). Diabetic hyperglycemia was associated with the greatest increase in steady-state MD cell Ca2+ level compared to control (2.4±0.2 and 1.1±0.1, respectively). RNA seq analysis revealed enrichment of numerous genes involved in membrane depolarization and pacemaker activity, such as voltage-dependent sodium, potassium, and calcium channels (Scn4b, Scn2b, Kcnd3, Kcnc2, Cacna1d), in afterhyperpolarization (Kcnn2), in the initiation of pacemaker activity (Itpr1), and in synapse formation and transmission (Nsg2, Tmem158, Syt5-13, Sv2a).

Conclusion

This study uncovered new neuron-like functional and molecular features of MD cells and established them as chief sensory neuroepithelial cells that form a nephron-level autonomous neuronal network to control key organ and somatosensory functions.

Funding

  • NIDDK Support