Abstract 084: Activation Of Trpv1-expressing Renal Sensory Nerves With N-oleoyldopamine Attenuates High Fat Diet-induced Impairment In Renal Function

Abstract

Renal injury occurs in obesity. Accumulating evidence indicates that activation of the transient receptor potential vanilloid 1 (TRPV1) protects tissues from injury albeit the mechanisms are largely unknown. We test the hypothesis that high fat diet (HFD) intake impairs afferent renal nerves expressing TRPV1 channels, leading to increased renal sympathetic nerve activity (RSNA), decreased renal function, and hypertension, and that chronic activation of TRPV1 positive afferent renal nerves attenuates HFD-induced impairment. N-oleoyldopamine (OLDA, 1 ng/kg, daily), a selective TRPV1 agonist, was administrated intrathecally (T8-L3) via a indwelled catheter to chronically activate TRPV1 positive afferent renal nerves in rats fed a HFD or normal fat diet (Con) for 8 weeks. HFD decreased renal TRPV1 expression and afferent renal nerve activity (ARNA, Con: 133±8, Con+OLDA: 127±15, HFD: 84±5, HFD+OLDA: 115±7, p<0.05) in response to intra-pelvis perfusion of capsaicin (4 μM, 3 min, 20 ml/min), a selective TRPV1 agonist, which were prevented by OLDA. HFD increased RSNA responses to intrathecal injection of muscimol (3 nmol/kg), a GABA-A receptor agonist, and urinary norepinephrine levels, which were prevented by OLDA. HFD decreased creatinine clearance and increased urinary albumin levels, which were prevented by OLDA (Creatinine clearance, Con: 0.52±0.09, Con+OLDA: 0.54±0.12, HFD: 0.24±0.04, HFD+OLDA: 0.40±0.06 ml/min/100 gbwt, p<0.05). HFD increased levels of collagen deposition, connective tissue growth factor (CTGF), and matrix metalloproteinase-2 (MMP-2) in the kidney, which were prevented by OLDA. HFD increased systolic blood pressure by the week of 6 after HFD, which was prevented by OLDA. Thus, HFD impairs TRPV1-positive afferent renal nerves, increases renal sympathetic nerve activity, and leads to renal injury and hypertension. Segment-specific intrathecal injection of OLDA protects against HFD-induced impairment in afferent renal nerves and prevents HFD-induced renal injury and hypertension. Our data illustrate that preservation of TRPV1 positive afferent renal nerves may be a therapeutic strategy in preventing obesity- or type 2 diabetes-induced renal injury and hypertension.