The role of atypical smooth muscle cells and Kᵥ7⁺ cells in peristalsis of the upper urinary tract

Abstract

Over the last 30 years, evidence has indicated the pacemaker cells driving pyeloureteric peristalsis through the upper urinary tract (UUT) are specialized smooth muscle cells called ‘atypical’ smooth muscle cells (ASMCs) interspersed at the base of the papilla near the papilla kidney border. The fundamental pacemaker signal of these ASMCs is suggested to be spontaneous transient depolarisations (STDs), which sum to trigger action potential discharge in the smooth muscle wall. These STDs arise from the opening of inward current channels activated by transient increases in internal ([Ca²⁺]i) as Ca²⁺ is released from both IP3 and ryanodine-receptor coupled Ca²⁺ stores (Lang et al., 2007a; Iqbal et al., 2012). This is typical of ‘Ca²⁺ oscillator’ models of generating regular rises of [Ca²⁺]i that contribute to a number of processes such as cardiac and smooth muscle contraction, secretion and DNA transcription. However, it is now apparent that this model of autorhythmicity is not sufficient to fully describe the pacemaker activity driving pyeloureteric peristalsis. Serosal interstitial cells (SICs) expressing Kᵥ7/KCNQ (‘M’ channel) currents (Iqbal et al. 2012), not present in smooth muscle cells (SMCs) also appear to be fundamentally involved in pyeloureteric pacemaking (Lang et al., 2012). These cells are located in the serosa adjacent to the smooth muscle wall and they increase in number with distance from the papilla-kidney junction (PKJ) (Iqbal et al., 2012). The use of Kᵥ7 channel blockers (XE991, linopirdine) and activators (flupirtine, meclofenamic acid) increased and decreased, respectively, the frequency of muscle wall contraction and associated action potential discharge without changing their time course. This was consistent with typical smooth muscle cells (TSMCs) not expressing these channels. Thus, these Kᵥ7.5⁺ SICs represent a precedent of a cell population within the renal pelvis, other than ASMCs, that have a direct modulating effect on pyeloureteric peristalsis. We have also confirmed the presence of cells positive for the hyperpolarisation-activated cyclic nucleotide-gated cation channel subunit 3 (HCN3⁺) (depolarising channels) a marker for the cardiac pacemaking current (Herrmann et al., 2011) in the same region as ASMCs of the renal pelvis of adult mice and demonstrated that two HCN channel blockers, ZD7288 and Cs⁺, reduced the frequency of peristaltic contractions and ASMC Ca²⁺ transients. However, slow-developing HCN currents, usually recorded upon the application of long duration hyperpolarisations, have not yet been observed in either TSMCs or ASMCs (Iqbal et al., 2012). This suggests that while HCN3⁺ cells may be ASMCs, any HCN channel current present only contributes to the resting membrane conductance. The activity of the Kᵥ7.5⁺ SICs appears to stabilise the resting membrane potential of cells in the pelvic wall, preventing large voltage swings and cytotoxic rises in [Ca²⁺]i upon either excessive Ca²⁺ entry through membrane channels or the inappropriate release from internal stores. In addition, we speculate that pyeloureteric pacemaking in rodents involves an interplay between Kᵥ7.5⁺ SICs and ASMCs in the renal pelvis especially during the immediate postnatal period when there is a rapid outgrowth of the renal pelvis and proliferation of SMCs in the pelvic wall. We suggest that this interplay is altered during perinatal development and reverses during functional obstruction. If this is the case in humans, SICs may well represent potential therapeutic targets in the early (in utero/neonatal) clinical intervention of perinatal congenital obstructive hydronephrosis. Additional material(s) submitted with thesis.