Abstract P231: High Fat Diet-induced Er Stress and Inflammation in the Kidney: Role of Trpv1-positive Afferent Renal Nerves

Chronic high fat diet (HFD) intake may lead to enhancement in endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and inflammation in the kidney, but the mechanisms of HD effects are largely unknown. This study tests the hypothesis that HFD impairs afferent renal nerves expressing the transient receptor potential vanilloid 1 (TRPV1) channels, and that stimulating/preserving TRPV1-positive afferent renal nerves prevents against HFD-induced increases in ER stress, ROS production, and inflammation in the kidney. HFD decreased levels of TRPV1 in the kidney, levels of urinary calcitonin-gene related peptide (CGRP) and substance P (SP), and responses of afferent renal nerve activity (ARNA) to capsaicin, a TRPV1 agonist, perfused into the renal pelvis. HFD increased ER stress (XBP-1, CREB2, GRP78, p-JNK), ROS production (urinary 8-isoprostane), and inflammation (TNF-α, IL-1β) in the kidney. N-oleoyldopamine (OLDA, a TRPV1 agonist, 1 ng/kg, daily) or vehicle was given intrathecally (i.t.) via indwelled catheters to segments (T8-L3) supplying the kidneys of rats fed a HFD or normal fat diet (Con) for 8 weeks. OLDA prevented HFD-induced decreases in the levels of renal TRPV1, urinary CGRP and SP, and ARNA responses to capsaicin, as well as HFD-induced increases in renal ER stress, ROS production, and inflammation. OLDA-induced protection during HFD was abolished by degeneration of TRPV1-positive afferent renal nerves by topical application of resiniferatoxin (RTX, 2 μg/ml x 2 times), a potent TRPV1 agonist, on renal nerves (TNF-α, Con: 0.17±0.02, HFD: 0.41±0.03, HFD+OLDA: 0.21±0.02, HFD+OLDA+RTX: 0.46±0.04, p<0.05; 8-isoprostane, Con: 8.8±1.2, HFD: 17±2, HFD+OLDA: 11±1, HFD+OLDA+RTX: 22±3 ng/day, p<0.05). Thus, our data show that HFD impairs TRPV1-positive afferent renal nerves, and chronic stimulation of TRPV1 via intrathecal injection of OLDA to T8-L3 segments preserves TRPV1-positive afferent renal nerves to against HFD-induced ER stress, ROS production, and inflammation in the kidney given that impairment of this population of afferent renal nerves abolishes OLDA effects. These data indicate that TRPV1-positive afferent renal nerves play a counteractive role against HFD-induced renal injury.