Abstract 537: Segment-specific Intrathecal Injection of Metformin Protects Against High Fat Diet-induced Impairment in Afferent Renal Nerves and Renal Function

Abstract

Metformin (Met), a drug for treating type 2 diabetes by suppressing glucose production and increasing insulin sensitivity, may possess neuroprotective and neurogenesis effects. We test the hypotheses 1) that high fat diet (HFD) intake impairs afferent renal nerves expressing transient receptor potential vanilloid 1 (TRPV1) channels, leading to increased efferent renal nerve activity (ERNA), decreased renal function, and hypertension; and 2) that Met given intrathecally (i.t.) to segments (T8-L3) supplying the kidney prevents HFD-induced impairment in afferent renal nerves, renal function, and hypertension. Met (1 ng/kg, i.t. daily) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Glucose or insulin tolerance was impaired to the same degree between rats fed HFD with and without Met treatment. HFD decreased renal TRPV1 expression, plasma levels of calcitonin gene-related peptide, and afferent renal nerve activity (ARNA, Con: 126±11, Met: 136±14, HFD: 77±7, HFD+Met: 121±8, p<0.05) in response to intra-pelvis perfusion of capsaicin (a TRPV1 agonist at 4 mM, 3 min, 20 ml/min), which were prevented by Met. HFD increased renal tyrosine hydroxylase contents, ERNA responses to intrathecal injection of muscimol (a GABA-A receptor agonist at 3 nmol/kg), and urinary norepinephrine levels, which were prevented by Met. HFD decreased creatinine clearance (Con: 0.40±0.04, Met: 0.52±0.07, HFD: 0.12±0.05, HFD+Met: 0.30±0.04 ml/min/100 gbwt, p<0.05) and urinary Na+ excretion, and increased levels of urinary albumin, plasma urea, renal collagen deposition, renal connective tissue growth factor, and systolic blood pressure (Con: 132±1, Met: 130±1, HFD: 145±3, HFD+Met: 132±1 mmHg, p<0.05), which were prevented or attenuated by Met. Thus, HFD impairs TRPV1-positive afferent renal nerves and renal function, and increases renal sympathetic nerve activity and blood pressure. Segment-specific intrathecal injection of Met protects against HFD-induced impairment in afferent renal nerves and renal function, and prevents HFD-induced hypertension.