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1.
Kidney Int ; 105(1): 65-83, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37774921

RESUMO

Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.


Assuntos
Nefropatias , Podócitos , Camundongos , Animais , Inflamassomos/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Resposta ao Choque Frio , Rim/metabolismo , Podócitos/metabolismo , Nefropatias/metabolismo , Inflamação/metabolismo
2.
Nat Commun ; 15(1): 7963, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39261453

RESUMO

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin ß1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin ß1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin ß1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.


Assuntos
Senescência Celular , Nefropatias Diabéticas , Fator XII , Integrina beta1 , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Animais , Feminino , Humanos , Masculino , Camundongos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Fator XII/metabolismo , Fator XII/genética , Integrina beta1/metabolismo , Integrina beta1/genética , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Receptores de Ativador de Plasminogênio Tipo Uroquinase/genética , Transdução de Sinais
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