Activation of TRPV1-Expressing Renal Sensory Nerves of Rats with N-Oleoyldopamine Attenuates High-Fat-Diet-Induced Impairment of Renal Function

Abstract

Enhanced renal sympathetic nerve activity (RSNA) contributes to obesity-induced renal disease, while the role of afferent renal nerve activity (ARNA) is not fully understood. The present study tested the hypothesis that activating the transient receptor potential vanilloid 1 (TRPV1) channel in afferent renal nerves suppresses RSNA and prevents renal dysfunction and hypertension in obese rats. N-oleoyldopamine (OLDA, 1 ng/kg, daily) was administrated intrathecally (T8-L3) via an indwelled catheter to chronically activate, TRPV1-positive afferent renal nerves in rats fed a chow diet or high-fat diet (HFD) for 8 weeks. HFD intake significantly increased the body weight, impaired glucose and insulin tolerance, decreased creatinine clearance, and elevated systolic blood pressure in rats compared with the levels of the chow-fed rats (all p < 0.05). An intrathecal OLDA treatment for 8 weeks did not affect the fasting glucose level, glucose tolerance, and insulin tolerance in rats fed either chow or HFD. As expected, the chronic OLDA treatment significantly increased the levels of plasma calcitonin gene-related peptide and substance P and ARNA in the HFD-fed rats (all p < 0.05). Interestingly, the OLDA treatment decreased the urinary norepinephrine level and RSNA in rats fed HFD (both p < 0.05). Importantly, the OLDA treatment attenuated HFD-induced decreases in creatinine clearance and urinary Na⁺ excretion and increases in the plasma urea level, urinary albumin level, and systolic blood pressure at the end of an 8-week treatment (all p < 0.05). Taken together, the intrathecal administration of OLDA ameliorates the enhancement of RSNA, renal dysfunction, and hypertension in obese rats. These findings shed light on the roles of TRPV1-positive renal afferent nerves in obesity-related renal dysfunction and hypertension.

Keywords: N-oleoyldopamine; TRPV1; high-fat diet; hypertension; obesity.

Figure 1

Effects of OLDA on glucose and insulin tolerance. The glucose tolerance test (A) and insulin tolerance test (B) in rats fed chow diet or high-fat diet (HFD) by the end of the 8 week treatment with or without intrathecal N-oleoyldopamine (OLDA) treatment (1 ng/kg, daily). Blood from the tail was collected to measure the level of blood glucose before and after intraperitoneal injection of glucose (2 g/kg) in rats with 15 h fasting or insulin (0.75 IU/kg) in rats with 6 h fasting, respectively. Values are means ± SE (n = 8). * p < 0.05 compared with that of the chow group.

Figure 2

Effects of OLDA on afferent renal nerve function. The levels of plasma calcitonin gene-related peptide (CGRP) (A), substance P (SP) (B), and afferent renal nerve activity (ARNA) (C) response to intra-pelvis administration of capsaicin in chow-fed or high-fat-diet (HFD)-fed rats after 8 week of treatment with or without intrathecal N-oleoyldopamine (OLDA) treatment (1 ng/kg, daily). Values are means ± SE (n = 8). * p < 0.05 compared with that of the chow group; # p < 0.05 compared with that of the HFD group.

Figure 3

Effects of OLDA on renal sympathetic nerve activity. The renal sympathetic nerve activity (RSNA) response to intrathecal administration of muscimol (A) and the level of urinary norepinephrine (B) in chow-fed or high-fat-diet (HFD)-fed rats after 8 week of treatment with or without intrathecal N-oleoyldopamine (OLDA) treatment (1 ng/kg, daily). Values are means ± SE (n = 8). * p < 0.05 compared with that of the chow group; # p < 0.05 compared with that of the HFD group.

Figure 4

Effects of OLDA on renal function. Creatinine clearance (A), plasma urea level (B), urinary albumin excretion (C), and urinary sodium excretion (D) in chow-fed or high-fat-diet (HFD)-fed rats after 8 week of treatment with or without intrathecal N-oleoyldopamine (OLDA) treatment (1 ng/kg, daily). Values are means ± SE (n = 8). * p < 0.05 compared with that of the chow group; # p < 0.05 compared with that of the HFD group.

Figure 5

Effects of OLDA on systolic blood pressure. Tail-cuff systolic blood pressure in chow-fed or high-fat-diet (HFD)-fed rats during 8 week of treatment with or without intrathecal N-oleoyldopamine (OLDA) treatment (1 ng/kg, daily). Values are means ± SE (n = 8). * p < 0.05 compared with that of the chow group.