Propagation of Pacemaker Activity and Peristaltic Contractions in the Mouse Renal Pelvis Rely on Ca2+-activated Cl− Channels and T-Type Ca2+ Channels

Abstract

The process of urine removal from the kidney occurs via the renal pelvis. The renal pelvis demarcates the beginning of the upper urinary tract and is endowed with smooth muscle cells. Along the renal pelvis, organized contraction of smooth muscle cells generates the force required to move urine boluses towards the ureters and bladder. This process is mediated by specialized pacemaker cells that are highly expressed in the proximal renal pelvis that generate spontaneous rhythmic electrical activity to drive smooth muscle depolarization. The mechanisms by which peristaltic contractions propagate from the proximal to distal renal pelvis are not fully understood. In this study, we utilized a transgenic mouse that expresses the genetically encoded Ca2+ indicator, GCaMP3, under a myosin heavy chain promotor to visualize spreading peristaltic contractions in high spatial detail. Using this approach, we discovered variable effects of L-type Ca2+ channel antagonists on contraction parameters. Inhibition of T-Type Ca2+ channels reduced the frequency and propagation distance of contractions. Similarly, antagonizing Ca2+-activated Cl− channels or altering the transmembrane Cl− gradient decreased contractile frequency and significantly inhibited peristaltic propagation. These data suggest that voltage gated Ca2+ channels are important determinants of contraction initiation and maintain the fidelity of peristalsis as the spreading contraction moves further towards the ureter. Recruitment of Ca2+-activated Cl− channels, likely Anoctamin-1, and T-Type Ca2+ channels are required for efficiently conducting the depolarizing current throughout the length of the renal pelvis. These mechanisms are necessary for the efficient removal of urine from the kidney.

Characterization of the cellular components of mouse collecting lymphatic vessels reveals that lymphatic muscle cells are the innate pacemaker cells regulating lymphatic contractions

“…Furthermore, computational models have proposed LMC sarcoplasmic reticulum (SR) Ca 2+ release as the oscillator mechanism driving pacemaking (Imtiaz et al, 2007). SR Ca 2+ release has also been implicated in pericyte regulation of arterioles (Hashitani et al, 2015; van Helden and Imtiaz, 2019), in microvascular vasomotion (Boedtkjer et al, 2008; Aalkjaer et al, 2011; van Helden and Imtiaz, 2019), and in the contraction waves of atypical muscle cells of the lower urinary tract (Grainger et al, 2022).…”