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Aggravated renal inflammatory responses in TRPV1 gene knockout mice subjected to DOCA-salt hypertension
1Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
Abstract:
To test the hypothesis that deletion of the transient receptor potential vanilloid type 1 (TRPV1) channel exaggerates hypertension-induced renal inflammatory response, wild-type (WT) or TRPV1-null mutant (TRPV1(-/-)) mice were subjected to uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 wk. Mean arterial pressure (MAP) determined by radiotelemetry increased in DOCA-salt-treated WT or TRPV1(-/-) mice, whereas there was no difference in MAP between two strains at the baseline or after DOCA-salt treatment. DOCA-salt treatment increased urinary excretion of albumin and 8-isoprostane in both WT and TRPV1(-/-) mice, and the increases were greater in magnitude in the latter strain. Periodic acid-Schiff and Mason's trichrome staining showed that kidneys of DOCA-salt-treated TRPV1(-/-) mice exhibited more severe glomerulosclerosis and tubulointerstitial injury compared with DOCA-salt-treated WT mice. NF-kappaB assay showed that DOCA-salt treatment increased renal activated NF-kappaB concentrations in TRPV1(-/-) mice compared with WT mice. Immunostaining and ELISA assay revealed that DOCA-salt-treated TRPV1(-/-) mice had enhanced renal infiltration of monocyte/macrophage and lymphocyte, as well as increased renal levels of proinflammatory cytokine (TNF-alpha, IL-6) and chemokine (MCP-1) compared with DOCA-salt-treated WT mice. Renal ICAM-1 but not VCAM-1 expression was also greater in DOCA-salt-treated TRPV1(-/-) than WT mice. Dexamethasone (DEXA), an immunosuppressive drug, conveyed a renoprotective effect that was greater in DOCA-salt-treated TRPV1(-/-) compared with WT mice. These data show that renal inflammation is exacerbated in DOCA-salt hypertension when TRPV1 gene is deleted and that the deterioration is ameliorated by DEXA treatment, indicating that TRPV1 may act as a potential regulator of the inflammatory process to lessen renal injury in DOCA-salt hypertension.
Insights
Deleting the TRPV1 channel worsens kidney inflammation and injury in hypertension. However, dexamethasone treatment showed greater protective effects in these mice, suggesting TRPV1
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Hypertension is a major risk factor for chronic kidney disease.
- The transient receptor potential vanilloid type 1 (TRPV1) channel's role in hypertension-induced renal inflammation is not fully understood.
- TRPV1 channels are involved in pain sensation and inflammation.
Purpose of the Study:
- To investigate the hypothesis that deletion of the TRPV1 channel exacerbates hypertension-induced renal inflammatory response.
- To assess the impact of TRPV1 deletion on renal injury and inflammation markers in a mouse model of hypertension.
- To evaluate the renoprotective effect of dexamethasone in the absence of TRPV1.
Main Methods:
- Wild-type (WT) and TRPV1-null mutant (TRPV1(-/-)) mice underwent uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks.
- Mean arterial pressure (MAP) was monitored using radiotelemetry.
- Renal injury was assessed by histological staining (Periodic acid-Schiff, Mason's trichrome), and inflammatory markers (NF-kappaB, monocyte/macrophage, lymphocyte infiltration, TNF-alpha, IL-6, MCP-1, ICAM-1) were quantified using assays and immunostaining. Dexamethasone (DEXA) was administered to assess renoprotection.
Main Results:
- DOCA-salt treatment increased MAP in both WT and TRPV1(-/-) mice without significant differences between strains.
- TRPV1(-/-) mice exhibited exacerbated renal injury, including glomerulosclerosis and tubulointerstitial damage, along with increased urinary albumin and 8-isoprostane excretion compared to WT mice.
- Deletion of TRPV1 led to enhanced renal inflammation, characterized by increased NF-kappaB activation, immune cell infiltration, and elevated levels of pro-inflammatory cytokines (TNF-alpha, IL-6) and chemokines (MCP-1). Dexamethasone showed a greater renoprotective effect in TRPV1(-/-) mice.
Conclusions:
- Deletion of the TRPV1 gene exacerbates renal inflammation and injury in the context of DOCA-salt-induced hypertension.
- TRPV1 may play a protective role in mitigating renal damage during hypertension.
- The enhanced renoprotective effect of dexamethasone in TRPV1-null mice suggests a complex interplay between TRPV1 and immunosuppressive therapy in managing hypertensive kidney disease.
