Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy.
Diabetes Obes Metab
; 20(3): 698-708, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29106063
AIMS: To determine the specific role of podocyte-expressed cannabinoid-1 receptor (CB1 R) in the development of diabetic nephropathy (DN), relative to CB1 R in other renal cell types. MATERIAL AND METHODS: We developed a mouse model with a podocyte-specific deletion of CB1 R (pCB1Rko) and challenged this model with streptozotocin (STZ)-induced type-1 DN. We also assessed the podocyte response to high glucose in vitro and its effects on CB1 R activation. RESULTS: High glucose exposure for 48 hours led to an increase in CB1 R gene expression (CNR1) and endocannabinoid production in cultured human podocytes. This was associated with podocyte injury, reflected by decreased podocin and nephrin expression. These changes could be prevented by Cnr1-silencing, thus identifying CB1R as a key player in podocyte injury. After 12 weeks of chronic hyperglycaemia, STZ-treated pCB1Rko mice showed elevated blood glucose similar to that of their wild-type littermates. However, they displayed less albuminuria and less podocyte loss than STZ-treated wild-type mice. Unexpectedly, pCB1Rko mice also have milder tubular dysfunction, fibrosis and reduction of cortical microcirculation compared to wild-type controls, which is mediated, in part, by podocyte-derived endocannabinoids acting via CB1 R on proximal tubular cells. CONCLUSIONS: Activation of CB1 R in podocytes contributes to both glomerular and tubular dysfunction in type-1 DN, which highlights the therapeutic potential of peripheral CB1 R blockade.
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01-internacional
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MEDLINE
Assunto principal:
Receptores de Canabinoides
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Nefropatias Diabéticas
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Podócitos
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Glomérulos Renais
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Túbulos Renais Proximais
Limite:
Animals
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article