The transient receptor potential (TRP) vanilloid 4 (TRPV4) member of the TRP superfamily has recently been implicated in numerous physiological processes. In this study, we describe a small molecule TRPV4 channel activator, (N-, which we have used as a valuable tool in investigating the role of TRPV4 in the urinary bladder. GSK1016790A elicited Ca 2ϩ influx in mouse and human TRPV4-expressing human embryonic kidney (HEK) cells (EC 50 values of 18 and 2.1 nM, respectively), and it evoked a dose-dependent activation of TRPV4 whole-cell currents at concentrations above 1 nM. In contrast, the TRPV4 activator 4␣-phorbol 12,13-didecanoate (4␣-PDD) was 300-fold less potent than GSK1016790A in activating TRPV4 currents. TRPV4 mRNA was detected in urinary bladder smooth muscle (UBSM) and urothelium of TRPV4 ϩ/ϩ mouse bladders. Western blotting and immunohistochemistry demonstrated protein expression in both the UBSM and urothelium that was absent in TRPV4 Ϫ/Ϫ bladders. TRPV4 activation with GSK1016790A contracted TRPV4 ϩ/ϩ mouse bladders in vitro, both in the presence and absence of the urothelium, an effect that was undetected in TRPV4 Ϫ/Ϫ bladders. Consistent with the effects on TRPV4 HEK whole-cell currents, 4␣-PDD demonstrated a weak ability to contract bladder strips compared with GSK1016790A. In vivo, urodynamics in TRPV4 ϩ/ϩ and TRPV4 Ϫ/Ϫ mice revealed an enhanced bladder capacity in the TRPV4 Ϫ/Ϫ mice. Infusion of GSK1016790A into the bladders of TRPV4 ϩ/ϩ mice induced bladder overactivity with no effect in TRPV4 Ϫ/Ϫ mice. Overall TRPV4 plays an important role in urinary bladder function that includes an ability to contract the bladder as a result of the expression of TRPV4 in the UBSM.Transient receptor potential (TRP) vanilloid 4 (TRPV4), a member of the TRP superfamily of cation channels, has been implicated in a number of physiological processes, including osmoregulation (Liedtke and Friedman, 2003;Mizuno et al., 2003), hearing (Tabuchi et al., 2005), thermal and mechaniThis work was supported by GlaxoSmithKline Pharmaceuticals. Article, publication date, and citation information can be found at

Differentiation in the spore-forming bacterium Bacillus subtilis is governed by the sequential activation of five sporulation-specific transcription factors. The early mother-cell-specific transcription factor, s E , directs the transcription of many genes that contribute to the formation of mature, dormant spores. In this study, DNA microarrays were used to identify genes belonging to the s E regulon. In total, 171 genes were found to be under the control of s E . Of these, 101 genes had not previously been described as being s E dependent. Disruption of some of the previously unknown genes ( ydcC, yhaL, yhbH, yjaV and yqfD) resulted in a defect in sporulation.

The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

Renal T-cell infiltration is a key component of salt-sensitive hypertension in Dahl salt-sensitive rats. Here we use an electronic servo-control technique to determine the contribution of renal perfusion pressure to T-cell infiltration in the Dahl salt-sensitive rat kidney. An aortic balloon occluder placed around the aorta between the renal arteries was used to maintain perfusion pressure to the left kidney at control levels, approximately 128 mmHg, during 7-days of salt-induced hypertension while the right kidney was exposed to increased renal perfusion pressure which averaged 157 ± 4 mmHg by high salt day-7. The number of infiltrating T-cells was compared between the two kidneys. Renal T-cell infiltration was significantly blunted in the left servo-controlled kidney compared to the right uncontrolled kidney. The number of CD3+, CD3+CD4+ and CD3+CD8+ T-cells were all significantly lower in the left servo-controlled kidney. This effect was not specific to T-cells since CD45R+ (B-cells) and CD11b/c+ (monocytes and macrophages) cell infiltrations were all exacerbated in the hypertensive kidneys. Increased renal perfusion pressure was also associated with augmented renal injury, with increased protein casts and glomerular damage in the hypertensive kidney. Levels of norepinephrine were comparable between the two kidneys, suggestive of equivalent sympathetic innervation. Renal infiltration of T-cells was not reversed by the return of renal perfusion pressure to control levels after 7-days of salt-sensitive hypertension. We conclude that increased pressure contributes to the initiation of renal T-cell infiltration during the progression of salt-sensitive hypertension in Dahl salt-sensitive rats.

Supplemental Digital Content is available in the text.