TRPV1 Hyperfunction Contributes to Renal Inflammation in Oxalate Nephropathy.

Chien-Lin Lu,Te-Yi Teng,Ming-Chieh Ma,Min-Tser Liao

doi:10.3390/ijms22126204

Abstract

Inflammation worsens oxalate nephropathy by exacerbating tubular damage. The transient receptor potential vanilloid 1 (TRPV1) channel is present in kidney and has a polymodal sensing ability. Here, we tested whether TRPV1 plays a role in hyperoxaluria-induced renal inflammation. In TRPV1-expressed proximal tubular cells LLC-PK1, oxalate could induce cell damage in a time- and dose-dependent manner; this was associated with increased arachidonate 12-lipoxygenase (ALOX12) expression and synthesis of endovanilloid 12(S)-hydroxyeicosatetraenoic acid for TRPV1 activation. Inhibition of ALOX12 or TRPV1 attenuated oxalate-mediated cell damage. We further showed that increases in intracellular Ca2+ and protein kinase C α activation are downstream of TRPV1 for NADPH oxidase 4 upregulation and reactive oxygen species formation. These trigger tubular cell inflammation via increased NLR family pyrin domain-containing 3 expression, caspase-1 activation, and interleukin (IL)-1β release, and were alleviated by TRPV1 inhibition. Male hyperoxaluric rats demonstrated urinary supersaturation, tubular damage, and oxidative stress in a time-dependent manner. Chronic TRPV1 inhibition did not affect hyperoxaluria and urinary supersaturation, but markedly reduced tubular damage and calcium oxalate crystal deposition by lowering oxidative stress and inflammatory signaling. Taking all these results together, we conclude that TRPV1 hyperfunction contributes to oxalate-induced renal inflammation. Blunting TRPV1 function attenuates hyperoxaluric nephropathy.

Highlights

The transient receptor potential vanilloid 1 (TRPV1) channel is known as a polymodal sensor recognizing the presence of heat (>43 ◦C), acidosis, and irritating chemicals such as lipid metabolites, capsaicinoids, and oxygen radicals [1,2]
Inhibition of ALOX12 by a selective blocker, cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC), and TRPV1 by two specific blockers, capsazepine (Capz) and SB-366791 (SB), attenuated the tubulotoxicity of oxalate by lowering lactate dehydrogenase (LDH) release (Figure 1E). These results indicate that oxalate-induced tubular cell damage is dependent on the effects of ALOX12 and TRPV1
TRPV1 hyperfunction in oxalate-mediated nephropathy is further evidenced by in vivo observations showing that chronic TRPV1 inhibition markedly reduced hyperoxaluriainduced tubular damage and calcium oxalate (CaOx) crystal formation via inflammation

Summary

Introduction

The transient receptor potential vanilloid 1 (TRPV1) channel is known as a polymodal sensor recognizing the presence of heat (>43 ◦C), acidosis (pH < 5.9), and irritating chemicals such as lipid metabolites, capsaicinoids, and oxygen radicals [1,2]. In the sensory nervous system, TRPV1 integrates these noxious stimuli for induction of pain sensation. Aside from nociception, we previously showed a novel role of TRPV1 in the visceral sensation of the rat kidney, where it acts as a mechanoreceptor [3]. TRPV1 is located at the renal pelvic wall and expressed in the peripheral nerve endings of renal sensory nerves to trigger mechano-sensation during urine excretion. Activation of TRPV1-mediated renal sensory nerves reflexly reduces efferent renal sympathetic nerve activity and enhances urinary excretion in terms of the diuretic renorenal reflex [3]. We showed that TRPV1 is expressed in the renal tubules, with strong expression in the apical membrane [3]. The tubular expression of TRPV1 in the rat kidney was consistent with previous findings [4]

Methods

Results

Conclusion