Afferent neurons of the kidney with impaired firing pattern in inflammation - role of sodium currents?

Nena Lale; Tilmann Ditting; Karl F Hilgers; Peter Linz; Christian Ott; Roland E Schmieder; Mario Schiffer; Kerstin Amann; Roland Veelken; Kristina Rodionova

doi:10.1007/s00424-023-02852-6

Afferent neurons of the kidney with impaired firing pattern in inflammation - role of sodium currents?

Pflugers Arch. 2023 Nov;475(11):1329-1342. doi: 10.1007/s00424-023-02852-6. Epub 2023 Sep 6.

Authors

Nena Lale¹, Tilmann Ditting^{1

2}, Karl F Hilgers¹, Peter Linz³, Christian Ott^{1

2}, Roland E Schmieder¹, Mario Schiffer¹, Kerstin Amann⁴, Roland Veelken^{5

6}, Kristina Rodionova¹

Affiliations

¹ Department of Internal Medicine 4 Nephrology and Hypertension, Friedrich-Alexander University Erlangen, 91054, Erlangen, Germany.
² Department of Internal Medicine 4 - Nephrology and Hypertension, Paracelsus Private Medical School Nuremberg, Nuremberg, Germany.
³ Department of Radiology, Friedrich-Alexander University Erlangen, 91054, Erlangen, Germany.
⁴ Department of Nephropathology, Friedrich-Alexander University Erlangen, 91054, Erlangen, Germany.
⁵ Department of Internal Medicine 4 Nephrology and Hypertension, Friedrich-Alexander University Erlangen, 91054, Erlangen, Germany. roland.veelken@uk-erlangen.de.
⁶ Department of Internal Medicine 4 - Nephrology and Hypertension, Paracelsus Private Medical School Nuremberg, Nuremberg, Germany. roland.veelken@uk-erlangen.de.

Abstract

Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as "tonic," i.e., sustained action potential (AP) firing, or "phasic," i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na⁺ and K⁺ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na⁺ and K⁺ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na⁺ and K⁺ peak current density increased in phasic (Na⁺: - 969 ± 47 vs. - 758 ± 47 nA/pF, P < 0.01; K⁺: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na⁺ currents ([- 365- - 1429 nA] vs. [- 412- - 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na⁺ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.

Keywords: Chemokine; Firing pattern; Phasic; Renal afferent nerve; Sodium currents; Tonic; Voltage-gated sodium channels.