RESUMO
Hypertensive nephropathy (HTN) ranks as the second-leading cause of end-stage renal disease (ESRD). Accumulating evidence suggests that persistent hypertension injures tubular cells, leading to tubulointerstitial fibrosis (TIF), which is involved in the pathogenesis of HTN. G protein-coupled receptors (GPCRs) are implicated in many important pathological and physiological processes and act as important drug targets. In this study, we explored the intrarenal mechanisms underlying hypertension-associated TIF, and particularly, the potential role of GPR97, a member of the adhesion GPCR subfamily, in TIF. A deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mouse model was used. We revealed a significantly upregulated expression of GPR97 in the kidneys, especially in renal tubules, of the hypertensive mice and 10 patients with biopsy-proven hypertensive kidney injury. GPR97-/- mice showed markedly elevated blood pressure, which was comparable to that of wild-type mice following DOCA/salt treatment, but dramatically ameliorated renal injury and TIF. In NRK-52E cells, we demonstrated that knockdown of GPR97 suppressed the activation of TGF-ß signaling by disturbing small GTPase RhoA-mediated cytoskeletal reorganization, thus inhibiting clathrin-mediated endocytosis of TGF-ß receptors and subsequent Smad activation. Collectively, this study demonstrates that GPR97 contributes to hypertension-associated TIF at least in part by facilitating TGF-ß signaling, suggesting that GPR97 is a pivotal intrarenal factor for TIF progression under hypertensive conditions, and therapeutic strategies targeting GPR97 may improve the outcomes of patients with HTN.
Assuntos
Acetato de Desoxicorticosterona , Hipertensão Renal , Hipertensão , Camundongos , Animais , Acetato de Desoxicorticosterona/efeitos adversos , Rim/patologia , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/metabolismo , Hipertensão Renal/patologia , Hipertensão/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , FibroseRESUMO
Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule-like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell-specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin-dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.
Assuntos
Injúria Renal Aguda , Injúria Renal Aguda/patologia , Animais , Moléculas de Adesão Celular , Moléculas de Adesão Juncional/metabolismo , Rim/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Hirschsprung's disease is the congenital absence of generating the peristaltic contractions transmitting from the proximal colon to rectum. We previously have found that tetraethylammonium (TEA), the nonselective Ca(2+)-activated K(+) channel blocker, increases the maximal contractile force and the amplitude of the contraction in rat duodenum. The present study is to test the effect of TEA on motility of colon and rectum from rats and Hirschsprung's disease patients in vitro, in order to find an alternative method to improve the syndrome of Hirschsprung's disease. The rectal and colonic motility was recorded by a tension transducer connected to a biology function experiment system. Histology was analyzed with standard hematoxylin and eosin staining. TEA (1, 3, and 5 mM) significantly increased the amplitude and frequency of contractility of colon and rectum from rats in longitudinal and circular direction. TEA at 5 and 15 mM concentrations showed no effect on histology of colon and rectum from rats that were administered locally with TEA into colon lumen from anus for 10 days. TEA at 15 mM increased the amplitude and frequency of contractions of the colon and rectum from Hirschsprung's disease patients. Our data showed that TEA increased the contractility of colon and rectum from rats and Hirschsprung's disease patients in vitro, suggesting that local administration of TEA in colon or rectum lumen might be an alternative method to ameliorate the syndrome of Hirschsprung's disease patients who are not cured completely by surgery or not suitable for surgery.