Mechanosensitive modulation of peristaltic contractions in the mouse renal pelvis

The renal pelvis develops spontaneous phasic contractions (SPCs) that underlie pyeloureteric peristalsis. Increased urine flow into the renal pelvis mechanically stimulates the contractile machinery within the renal pelvis to facilitate the propagation of peristalsis. Here, the effects of mechanostimulation of the pelvicalyceal junction (PCJ), where SPCs originate from, on the properties of SPCs were investigated. Using the wire myograph, isometric tension changes in tubular preparations of mouse renal pelvis with calyces were circumferentially measured, while mechanostimuli were applied to the PCJ. Immunohistochemistry and intracellular Ca2+ imaging were performed, respectively, to investigate the distribution and functional roles of mechanosensitive TRPV4 channels in the renal pelvis. SPCs periodically originated from PCJ and propagated distally. Mechanostimulation of the PCJ reduced the frequency of SPCs by about 60%, while almost quadrupling their amplitude. Capsaicin (100 nM), an agonist of TRPV1 channels, or calcitonin gene-related peptide (CGRP) (30 nM) also slowed and enlarged SPCs. A prolonged pre-exposure to capsaicin or BIBN4096 (1 μM), a CGRP receptor antagonist, inhibited the mechanostimulation-induced reduction in the SPC frequency, but did not block the increase in SPC amplitude. TRPV4 immunoreactivity was expressed in both atypical (ASMCs) and typical smooth muscle cells (TSMCs). GSK1016790A (100 nM), a TRPV4 agonist, enlarged SPCs independently of TRPV1 or CGRP without increasing the amplitude of spontaneous Ca2+ transients in TSMCs. Thus, mechanostimulation of PCJ appears to activate TRPV1-expressing sensory nerves, releasing CGRP that predominantly reduce the SPC frequency. Activation of TRPV4 may be involved in the mechanosensitive enlargement of SPCs. (247 words).