RESUMO
BACKGROUND: The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown. METHODS: To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabetic db/db mice, mice with experimental Alport syndrome, C57BL/6 mice, and STING knockout mice to assess the role of the STING signaling pathway in kidney failure. RESULTS: In vitro, murine and human podocytes express all of the components of the cGAS-STING pathway. In vivo, activation of STING renders C57BL/6 mice susceptible to albuminuria and podocyte loss. STING is activated at baseline in mice with experimental DKD and Alport syndrome. STING activation occurs in the glomerular but not the tubulointerstitial compartment in association with autophagic podocyte death in Alport syndrome mice and with apoptotic podocyte death in DKD mouse models. Genetic or pharmacologic inhibition of STING protects from progression of kidney disease in mice with DKD and Alport syndrome and increases lifespan in Alport syndrome mice. CONCLUSION: The activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.
Assuntos
Nefropatias Diabéticas , Nefrite Hereditária , Podócitos , Camundongos , Humanos , Animais , Nefrite Hereditária/genética , Nefrite Hereditária/metabolismo , Camundongos Endogâmicos C57BL , Podócitos/metabolismo , Proteinúria/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Camundongos Knockout , Nucleotidiltransferases/metabolismoRESUMO
The acyl-CoA synthetase medium-chain family member 2 (Acsm2) gene was first identified and cloned by our group as a kidney-specific "KS" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction.
Assuntos
Coenzima A Ligases/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Mitocondriais/metabolismo , Injúria Renal Aguda/enzimologia , Injúria Renal Aguda/genética , Injúria Renal Aguda/patologia , Animais , Coenzima A Ligases/genética , Modelos Animais de Doenças , Células Epiteliais/patologia , Fibrose , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Renina/genética , Renina/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologiaRESUMO
Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.