TRPV1 hyperfunction impairs renal sensory response in the rat hyperoxaluric kidney
Ming-Chieh Ma1, Ho-Shiang Huang2
School of Medicine1, Fu Jen Catholic University, New Taipei City, Taiwan
Department of Urology2, National Cheng Kung University, Tainan, Taiwan;
Purpose: We previously demonstrated that renal sensory function in response to mechano- and chemo-stimulation was impaired in rat kidneys with hyperoxaluria and/or calcium oxalate (CaOx) crystals. The transient receptor potential vanilloid 1 channel (TRPV1) is known to present in rat kidneys and responsible for activation of afferent renal nerve activity (ARNA) and induction of diuretic renorenal reflex. The present study therefore tests whether TRPV1 dysfunction may be the underlying mechanism for contribution to sensory impairment seen in the hyperoxaluric kidney.
Materials and Methods: Acute hyperoxaluria was induced by intrapelvic perfusion of oxalate into renal pelvis, a tissue area mostly originated for renal sensory nerves. Chronic hyperoxaluria was induced in rats after fed with fed with 5% hydroxyl-L-proline (HP) in daily diet for 42 days. Renal nerves in the left kidney were carefully isolated for recording of ARNA and efferent renal sympathetic nerve activity (ERSNA). Changes in the cortical microvascular blood flow (CMBF) were monitored by ultrasonic flowmeter. Renorenal reflex response was tested by rising intrapelvic pressure (IPP) or intrapelvic perfusion of high salt solution in the left kidney, and urine output and sodium excretion in the contralateral (right) kidney were collected. Renal pelvic effluent was collected for determination of the amount of sensory neuropeptide substance P (SP) release. Changes in TRPV1 and neurokinin-1 receptor (NK-1R) expression in renal pelvis were examined by Western blot analysis.
Results: Compared to vehicle-treated kidney, acute perfusion of oxalate into renal pelvis resulted in persistently decreased ARNA, increased ERSNA, decreased CMBF, and impaired renorenal reflex after 4 h of treatment. SP release was increased after oxalate treatment, this associated with NK-1R downregulation. These however were attenuated by co-treatment of specific TRPV1 blocker SB-366791. As a polymodal sensor, our results indicate TRPV1 may act as an oxalate sensor. In HP rats, ARNA in response to chemo- and mechano-stimulation, and ARNA-mediated reflex control on ERSNA and renal excretion were impaired after 7 days of treatment and thereafter. Severe reductions were found after 42 days of hyperoxaluria with CaOx deposition. These associated with increases in TRPV1 expression and SP release, and NK-1R downregulation in renal pelvis.
Conclusion: Our results clearly indicate that TRPV1 hyperfunction contributes to renal sensory impairment in the hyperoxaluric rats, which led to too much SP release, and NK-1R desensitization in nerve endings of renal pelvis. Deficiency in renal sensation blinds the kidney to the presence of hyperoxaluria as well as the formation of CaOx.