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. 2014 Oct 17;9(10):e109842.
doi: 10.1371/journal.pone.0109842. eCollection 2014.

Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury

Lan Chen  1 , Lajos Markó  2 , Mario Kaßmann  2 , Ye Zhu  3 , Kaiyin Wu  4 , Maik Gollasch  3
Affiliations

Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury

Lan Chen et al. PLoS One. .

Erratum in

  • PLoS One. 2014;9(12):e115469

Abstract

Objectives: Transient receptor potential vanilloid 1 (TRPV1) -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist), capsazepine (TRPV1 antagonist) and using Trpv1-/- mice.

Methods and results: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight) or capsazepine (50 mg/kg body weight). Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL) abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE) or epoxyeicosatrienoic acids (EETs) are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI.

Conclusions: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Serum creatinine levels in mice subjected to renal I/R injury were ameliorated by pretreatment with capsaicin, but not capsazepine or genetic ablation of TRPV1.
Control, control mice that underwent sham surgery (nephrectomy) without I/R. I/R Control, control mice that underwent renal I/R injury. Capsaicin I/R, wild-type mice pretreated with capsaicin followed by renal I/R injury. Capsazepine I/R, wild-type mice pretreated with capsazepine followed by renal I/R injury. Trpv1−/− mice that underwent renal I/R injury. *P<0.05. P>0.05; not significant.
Figure 2
Figure 2. Amelioration of tubular damage score of I/R-induced AKI by pretreatment of mice with capsaicin, but not with capsazepine or genetic ablation of TRPV1.
Panel A: Tubular damage scores of ipsilateral kidneys (I/R Control) and kidneys after I/R (I/R) of control mice. Tubular damage scores of ipsilateral kidneys (Capsaicin C) and kidneys after I/R injury (Capsaicin I/R) of mice pretreated with capsaicin. Tubular damage scores of ipsilateral kidneys (Capsazepine C) and kidneys after I/R injury (Capsazepine I/R) of mice pretreated with capsazepine. Tubular damage scores of ipsilateral kidneys (Trpv1−/− C) and kidneys after I/R injury (Trpv1−/− I/R) of Trpv1−/− mice. Scores of ipsilateral control kidneys without I/R injury were all 0. *, P<0.05. P≥0.05; not significant. Panel B: Histological sections. (a) I/R Control, histology of ipsilateral kidney before renal I/R injury of a control mouse. (b) I/R, histology of kidney after I/R injury of a control mouse. The section shows acute tubular necrosis characterized by loss of tubular epithelial cells (arrow) and shedding of the brush border (asterisk). (c) Capsaicin I/R, histology of kidney after I/R injury of a mouse pretreated with capsaicin. Acute tubular necrosis (arrow). (d) Trpv1−/− I/R, histology of kidney after I/R injury of a Trpv1−/− mouse. Acute tubular necrosis (arrow) and shedding of the brush border (asterisk). Scale bar 100 µm. Magnification × 200.
Figure 3
Figure 3. NGAL abundance in the kidney was lower in I/R-induced AKI in mice treated with capsaicin, but not with capsazepine or in Trpv1−/− mice.
Panels A: NGAL abundance of ipsilateral kidneys (I/R Control) and kidneys after I/R (I/R) injury of control mice. NGAL abundance of ipsilateral kidneys (Capsaicin C) and kidneys after I/R injury (Capsaicin I/R) of mice pretreated with capsaicin. NGAL abundance of ipsilateral kidneys (Capsazepine C) and kidneys after I/R injury (Capsazepine I/R) of mice treated with capsazepine. NGAL abundance of ipsilateral kidneys (Trpv1−/− C) and kidneys after I/R injury (Trpv1−/− I/R) of Trpv1−/− mice. *, P<0.05. P>0.05; not significant. Panels B: Immunohistological sections. (a) I/R Control, images of NGAL negative staining of ipsilateral kidney before renal I/R injury of a control mouse. (b) I/R, intense renal NGAL staining after I/R injury of a control mouse. (c) Capsaicin I/R, renal NGAL staining after I/R injury of a mouse pretreated with capsaicin. (d) Trpv1−/− I/R, renal NGAL staining after I/R injury of a Trpv1−/− mouse. Scale bar 100 µm. Magnification ×200.
Figure 4
Figure 4. Lower Ly-6B.2 positive cells in the kidneys after I/R-induced AKI in mice treated with capsaicin, but not with capsazepine or in Trpv1−/− mice.
Ly-6B.2 positive cells were analyzed in the medulla (red color in panels B, marked by arrows). Panels A: Ly-6B.2 positive cells per field view in ipsilateral kidneys (I/R Control) and kidneys after I/R (I/R) injury of control mice. Ly-6B.2 positive cells in ipsilateral kidneys (Capsaicin C) and kidneys after I/R injury (Capsaicin I/R) of mice pretreated with capsaicin. Ly-6B.2 positive cells in ipsilateral kidneys (Capsazepine C) and kidneys after I/R injury (Capsazepine I/R) of mice treated with capsazepine. Ly-6B.2 positive cells in ipsilateral kidneys (Trpv1−/− C) and kidneys after I/R injury (Trpv1−/− I/R) of Trpv1−/− mice. *, P<0.05. P>0.05; not significant. Panels B: Immunohistological sections. (a) I/R Control, images of Ly-6B.2 positive cells in ipsilateral kidney before renal I/R injury of a control mouse. (b) I/R, Ly-6B.2 positive cells in a kidney after I/R injury of a control mouse. (c) Capsaicin I/R, Ly-6B.2 positive cells in a kidney after I/R injury of a mouse pretreated with capsaicin. (d) Trpv1−/− I/R, Ly-6B.2 positive cells in a kidney after I/R injury of a Trpv1−/− mouse. Scale bar 50 µm. Magnification ×400.
Figure 5
Figure 5. Eicosanoids and anandamide levels in non-ischemic (control) and ischemic (I) kidneys of (WT) wild-type mice after I-induced AKI.
5,6-EET, 5,6-epoxyeicosatrienoic acid; 8,9-EET, 8,9-epoxyeicosatrienoic acid; 11,12-EET, 11,12-epoxyeicosatrienoic acid; 14,15-EET, 14,15-epoxyeicosatrienoic acid; 5,6-DHET, 5,6-dihydroxyeicosastrienoic acid; 8,9-DHET, 8,9-dihydroxyeicosastrienoic acid; 11,12-DHET, 11,12-dihydroxyeicosastrienoic acid; 14,15-DHET, 14,15-dihydroxyeicosastrienoic acid; 20-HETE, 20-hydroxyeicosatetraenoic acid; 9,10-EPOME, 9(10)epoxy-9Z-octadecenoic acid; 12,13-EPOME, 12(13)epoxy-9Z-octadecenoic acid; 9,10-DIHOME, 9(10)-dihydroxy-12Z-octadecenoic acid; 9,10-DIHOME, 9(10)-dihydroxy-12Z-octadecenoic acid. n = 5 in each group.
Figure 6
Figure 6. Eicosanoids and anandamide levels in non-ischemic (I/R Control) and ischemic (I/R) kidneys of wild-type mice after I/R-induced AKI, in non-ischemic (Capsaicin C) and ischemic (Capsaicin I/R) kidneys of wild-type mice after I/R-induced AKI, and in non-ischemic (Trpv1−/− C) and ischemic (Trpv1−/− I/R) kidneys of Trpv1−/− mice after I/R-induced AKI. n>8 in each group.
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