Decreased expression of the epithelial Ca2+ channel TRPV5 and TRPV6 in human renal cell carcinoma associated with vitamin D receptor.

PURPOSE: We investigated the expression of epithelial Ca(2+) channel TRPV (transient receptor potential vanilloid subfamily) 5 and 6, and vitamin D receptor in primary human renal cell carcinoma and benign peritumor tissues, and assessed the possible association between TRPV5/6 and vitamin D receptor expression. MATERIALS AND METHODS: Fresh-frozen primary tumor and peritumor tissues from 27 patients diagnosed with renal cell carcinoma were analyzed for TRPV5/6 and vitamin D receptor expression by quantitative reverse transcriptase-polymerase chain reaction, Western blot and immunohistochemistry. RESULTS: Quantitative reverse transcriptase-polymerase chain reaction revealed that TRPV5/6 and vitamin D receptor expression was decreased 38.11, 4.44 and 3.20 times in renal cell carcinoma vs normal kidney tissue (p = 0.012, 0.002 and 0.020, respectively). Relatively higher expression was noted for chromophobe renal cell carcinoma than for the other renal cell carcinoma subtypes. Vitamin D receptor mRNA expression significantly correlated with that of TRPV6 (r = 0.508, p = 0.007) and TRPV5 (r = 0.697, p = 0.032) in renal cell carcinoma. Western blot showed results similar to those of reverse transcriptase-polymerase chain reaction. Different expression was detected between kidney and renal cell carcinoma tissue. Immunohistochemical analysis verified strong detection of TRPV5/6 and vitamin D receptor in distal nephrons but demonstrated weak or no immunostaining much more often in renal cell carcinoma. CONCLUSIONS: Decreased TRPV5/V6 expression was noted in renal cell carcinoma, which correlated with vitamin D receptor. Different expression was also detected among the different renal cell carcinoma histopathological subtypes. Our observations suggest that altered vitamin D receptor expression may be associated with renal cell carcinoma carcinogenesis via TRPV5/6.

The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: pathophysiology of voiding dysfunction and pharmacological therapy.

Normal lower urinary tract function consists of voiding and storage. During voiding, the pontine micturition reflex center orders the sacral parasympathetic nucleus to increase parasympathetic activity, resulting in urinary bladder detrusor contraction via activation of post-synaptic muscarinic receptors (M2/3) and in the relaxation of both urethral and prostatic smooth muscle by nitric oxide (NO). In addition, the rhabdosphincter relaxes by inhibition of the pudendal nucleus at the sacral portion. During the storage phase, increase in sympathetic activity relaxes the urinary bladder via activation of post-synaptic beta(3)-receptors and in the contraction of both urethral and prostatic smooth muscles via alpha(1)-adrenoceptor. Many factors influence voiding function, including lower urinary tract disorders (benign prostatic hyperplasia in males, urethral stricture) and neurological disorders (central and peripheral). Theories of pharmacotherapy for voiding dysfunction are 1) increase detrusor contractility and 2) decrease urethral resistance. The former includes agonists for muscarinic receptors and cholinesterase inhibitor; and the latter includes alpha(1)-adrenoceptor antagonists, NO donors, benzodiazepines, baclofen, dantrolene, and boturinum toxin.

Sensor Mechanism and Afferent Signal Transduction of the Urinary Bladder: Special Focus on transient receptor potential Ion Channels.

In the urine storage phase, mechanical stretch stimulates bladder afferents. These urinary bladder afferent sensory nerves consist of small diameter Aδ- and C-fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. The exact mechanisms that underline mechano-sensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g. TTX-resistant Na(+) channels, Kv channels and hyperpolarization-activated cyclic nucleotidegated cation channels, degenerin/epithelial Na+ channel), and receptors (e.g. TRPV1, TRPM8, TRPA1, P2X2/3, etc.) have been identified at bladder afferent terminals and have implicated in the generation and modulation of afferent signals, which are elcited by a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The mammalian transient receptor potential (TRP) family consists of 28 channels that can be subdivided into six different classes: TRPV (Vanilloid), TRPC (Canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 among TRPs has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels, ion channels, and receptors in the pathophysiology of the urogenital tract, and may provide a new strategy for the treatment of bladder dysfunction.