Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio-and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.This research was funded by FIS/FEDER funds (PI15/00298, CP14/00133, PI16/01900, PI18/01386, PI18/0133, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD- 3686 CIFRA2-CM. Salary support: ISCIII Miguel Servet to ABS and MDS-N, ISCIII Sara Borrell to JM-MM, REDinREN RD016/0009 to MF-B, and MICIU to JG-M

Regulated necrosis role in inflammation and repair in acute kidney injury

Acute kidney injury (AKI) frequently occurs in patients with chronic kidney disease (CKD) and in turn, may cause or accelerate CKD. Therapeutic options in AKI are limited and mostly relate to replacement of kidney function until the kidneys recover spontaneously. Furthermore, there is no treatment that prevents the AKI-to-CKD transition. Regulated necrosis has recently emerged as key player in kidney injury. Specifically, there is functional evidence for a role of necroptosis, ferroptosis or pyroptosis in AKI and the AKI-to-CKD progression. Regulated necrosis may be proinflammatory and immunogenic, triggering subsequent waves of regulated necrosis. In a paradigmatic murine nephrotoxic AKI model, a first wave of ferroptosis was followed by recruitment of inflammatory cytokines such as TWEAK that, in turn, triggered a secondary wave of necroptosis which led to persistent kidney injury and decreased kidney function. A correct understanding of the specific forms of regulated necrosis, their timing and intracellular molecular pathways may help design novel therapeutic strategies to prevent or treat AKI at different stages of the condition, thus improving patient survival and the AKI-to-CKD transition. We now review key regulated necrosis pathways and their role in AKI and the AKI-to-CKD transition both at the time of the initial insult and during the repair phase following AKI

RIPK3 and kidney disease

Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction motif (RHIM) domain which allows interactions with other RHIM-containing proteins and a kinase domain that allows phosphorylation of target proteins. RIPK3 may be activated through interaction with RHIM-containing proteins such as RIPK1, TRIF and DAI (ZBP1, DLM-1) or through RHIM-independent mechanisms in an alkaline intracellular pH. RIPK3 mediates necroptosis and promotes inflammation, independently of necroptosis, through either activation of NFκB or the inflammasome. There is in vivo preclinical evidence of the contribution of RIPK3 to both acute kidney injury (AKI) and chronic kidney disease (CKD) and to the AKI-to-CKD transition derived from RIPK3 deficient mice or the use of small molecule RIPK3 inhibitors. In these studies, RIPK3 targeting decreased inflammation but kidney injury improved only in some contexts. Clinical translation of these findings has been delayed by the potential of some small molecule inhibitors of RIPK3 kinase activity to trigger apoptotic cell death by inducing conformational changes of the protein. A better understanding of the conformational changes in RIPK3 that trigger apoptosis, dual RIPK3/RIPK1 inhibitors or repurposing of multiple kinase inhibitors such as dabrafenib may facilitate clinical development of the RIPK3 inhibition concept for diverse inflammatory diseases, including kidney diseases. Resumen: La proteína quinasa 3 que interactúa con el receptor (RIPK3) es una quinasa intracelular que se encuentra a medio camino entre la muerte celular y la inflamación. La RIPK3 contiene un dominio motivo de interacción homotípica de RIP (RHIM), que permite las interacciones con otras proteínas que contienen RHIM, y un dominio de quinasa que permite la fosforilación de las proteínas diana. La RIPK3 puede ser activada a través de la interacción con las proteínas que contienen RHIM tales como RIPK1, TRIF y DAI (ZBP1, DLM-1), o a través de mecanismos independientes de RHIM en un pH intracelular alcalino. La RIPK3 media en la necroptosis y promueve la inflamación, independientemente de la necroptosis, bien a través de la activación de NFκB, o del inflamasoma. Existe evidencia preclínica in vivo de la contribución de RIPK3 a la insuficiencia renal aguda (IRA) y la enfermedad renal crónica (ERC), así como a la transición IRA-ERC derivada de ratones con deficiencia de RIPK3 o del uso de pequeñas moléculas inhibidoras de RIPK3. En dichos estudios, el tener a RIPK3 como objetivo redujo la inflamación, pero la nefropatía mejoró solo en algunos contextos. La traducción clínica de estos hallazgos se ha demorado debido al potencial de ciertas pequeñas moléculas inhibidoras de la actividad de la quinasa RIPK3 para activar la muerte celular induciendo cambios conformacionales de la proteína. Comprender mejor los cambios conformacionales de RIPK3 activadores de la apoptosis, los inhibidores duales RIPK3/RIPK1 o la reconversión de múltiples inhibidores de la quinasa tales como dabrafenib podría facilitar el desarrollo clínico del concepto de la inhibición de RIPK3 para diversas enfermedades inflamatorias, incluyendo las enfermedades renales