Deletion of transient receptor potential vanilloid type 1 receptors exaggerates renal damage in deoxycorticosterone acetate-salt hypertension

Abstract

To determine whether the transient receptor potential vanilloid type 1 (TRPV1) channel provides protection against hypertension-induced renal damage, hypertension was induced by uninephrectomy and by giving deoxycorticosterone acetate (DOCA)-salt in wild-type (WT) and TRPV1-null mutant (TRPV1-/-) mice. Mean arterial pressure, as determined by radiotelemetry, increased significantly and reached the peak 7 days after DOCA-salt treatment in both WT and TRPV1-/- mice. There was no difference in mean arterial pressure between the 2 strains at the baseline or at the peak that lasted for 4 treatment weeks. DOCA-salt treatment in both WT and TRPV1-/- mice led to increased urinary excretion of albumin and 8-isoprostane, glomerulosclerosis, renal cortical tubulointerstitial injury, tubulointerstitial fibrosis, increased number of tubular proliferating cell nuclear antigen-positive cells, and renal monocyte/macrophage infiltration, all of which were much more severe in DOCA-salt-treated TRPV1-/- compared with DOCA-salt-treated WT mice. Renal TRPV1 protein expression, but not the renal anandamide content, was elevated in DOCA-salt-treated WT compared with vehicle-treated WT mice. Renal anandamide levels were markedly elevated in DOCA-salt-treated TRPV1-/- but not in vehicle-treated TRPV1-/- mice. Thus, our data show that ablation of the TRPV1 gene exacerbates renal damage induced by DOCA-salt hypertension, indicating that TRPV1 may constitute a protective mechanism against end-organ damage induced by hypertension.

Figure 1

Effect of deoxycorticosterone acetate (DOCA)-salt treatment on blood pressure and heart rate, as determined by radiotelemetry, in wild type (WT) and TRPV1-null mutant (TRPV1^-/-) mice. A and B: Representative telemetric recording of blood pressure and heart rate in WT (A) and TRPV1^-/- (B) mice. C and D: Graphs representing daily average 24-hour mean arterial pressure (C) and heart rate (D). Values are mean ± SE (n=6).

Figure 2

Effect of deoxycorticosterone acetate (DOCA)-salt treatment on renal morphology in wild type (WT) and TRPV1-null mutant (TRPV1^-/-) mice. A and B: Periodic acid-Schiff (A) or Masson’s trichrome (B) stained kidney sections showing glomerular or cortical tubulointerstitial morphological changes in control WT and TRPV1^-/- mice (a and b), and WT and TRPV1^-/- mice (c and d) treated for 4 weeks with DOCA-salt. Magnification ×400 (A) or ×200 (B). C and D: Immunohistochemical stained sections from the kidney cortex demonstrating proliferating cell nuclear antigen (PCNA)-positive cells (in brown) (C) or F4/80-positive cells (monocytes/macrophages in red) (D) in the renal cortex of control WT and TRPV1^-/- mice (a and b), and WT and TRPV1^-/- mice (c and d) treated for 4 weeks with DOCA-salt. Magnification ×400.

Figure 3

Effect of deoxycorticosterone acetate (DOCA)-salt treatment on renal glomerular and cortical tubulointerstitial injury in wild type (WT) and TRPV1-null mutant (TRPV1^-/-) mice. A: Graph presenting the average of glomerulosclerosis index. B: Graph presenting the changes in mesangial matrix of glomeruli. C: Graph presenting the average of tubulointerstitial injury score. D: Graph presenting the changes in renal collagen levels. Values are mean ± SE (n=7 to 8). *P<0.05 compared with control WT or TRPV1^-/- mice; †P<0.05 compared with DOCA-salt-treated WT mice.

Figure 4

Effect of deoxycorticosterone acetate (DOCA)-salt treatment on renal cortex cell proliferation and monocyte/macrophage infiltration in wild type (WT) and TRPV1-null mutant (TRPV1^-/-) mice. A: Graph presenting the mean value of PCNA-positive cells in the renal cortex. B: Graph presenting F4/80-positive cells (monocyte/macrophage) in the renal cortex. The results are expressed as cells per square millimeter. Values are mean ± SE (n=7 to 8). *P<0.05 compared with control WT or TRPV1^-/- mice; †P<0.05 compared with DOCA-salt-treated WT mice.

Figure 5

Effect of deoxycorticosterone acetate (DOCA)-salt treatment on renal anandamide levels (A) and TRPV1 protein expression (B) in wild type (WT) or TRPV1-null mutant (TRPV1^-/-) mice. Values are mean ± SE (n=5 to 7). *P<0.05 compared with control WT or TRPV1^-/- mice; †P<0.05 compared with DOCA-salt-treated WT mice.