Abstract Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD. 

https://www.nature.com/articles/s41392-022-01036-5.pdf

Signaling pathways of chronic kidney diseases, implications for therapeutics

Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1β and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.

/pdf/pyroptosis-a-new-frontier-in-kidney-diseases-tbkqcxpryg.pdf

Pyroptosis: A New Frontier in Kidney Diseases

Intervertebral disc degeneration (IDD), being the predominant root cause of lower back pain, has led to an enormous socioeconomic burden in the world. Ferroptosis is an iron-dependent nonapoptotic and nonpyroptotic programmed cell death associated with an increase in reactive oxygen species (ROS), which has been implicated in the pathogenesis of IDD. Activation transcription factor 3 (ATF3) is widely reported to promote ferroptosis and apoptosis in multiple diseases, but its roles and underlying regulatory mechanism in IDD have not been identified. FAoptosis is defined as a mixed cell death consisting of ferroptosis and apoptosis. The loss- and gain-of-function experiments demonstrated that ATF3 positively regulated tert-butyl hydroperoxide- (TBHP-) induced nucleus pulposus cell (NPC) FAoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation. Furthermore, silencing ATF3 ameliorated the progression of IDD in vivo, whereas its overexpression showed the opposite phenotype. Bioinformatics analysis and molecular experiments corroborated that ATF3 is a direct target of miR-874-3p, suggesting that the upregulation of ATF3 in IDD might be caused at least in part due to the downregulation of miR-874-3p in IDD, thereby relieving the inhibition of ATF3 by miR-874-3p. The findings revealed that ATF3 has the potential to be used as a promising therapeutic target against IDD.

/pdf/silencing-atf3-might-delay-tbhp-induced-intervertebral-disc-2zq7ifki.pdf

Silencing ATF3 Might Delay TBHP-Induced Intervertebral Disc Degeneration by Repressing NPC Ferroptosis, Apoptosis, and ECM Degradation

Pyroptosis, a newly identified type of lytic programmed cell death (PCD), is featured in pore formation in the plasma membrane, swelling, and cell rupture with secretion of cellular contents, especially the inflammatory cytokines. A large number of studies have shown that pyroptosis includes not only the GSDMD involved caspase-1-dependent classical pathway and caspase-11/4/5-dependent non-classical pathway, but also the GSDME involved caspase-3 (Casp3) dependent pathway. Diabetic nephropathy (DN) is one of the most serious microvascular complications in diabetes. Present evidence suggestes that pyroptosis promotes the progression of several diabetic complications including DN. The underlying mechanism mediating renoprotection conferred by GSDME regulation in the diabetic kidney, specifically in human tubular cells has been investigated. Z-DEVD-FMK, the inhibitor of Casp3, ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVDFMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stimulated HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Based on this, it is not difficult to conclude that therapies targeting Casp3/GSDME dependent pyroptosis show great application prospects in DN, and novel nephroprotective strategy using GSDME-derived peptides directed against Casp3-induced cell death in vitro and in vivo may be a key breakthrough for this goal. Therefore, in the mini-review, we introduced the history of pyroptosis; gasdermin family proteins especially GSDME, and GSDME mediated pyroptosis in DN, expecting this novel mechanism may provide valuable therapeutic insights for the treatment of DN.

Mini-Review: GSDME-Mediated Pyroptosis in Diabetic Nephropathy

Pyroptosis in Kidney Disease.

Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.

/pdf/gsdme-mediated-pyroptosis-promotes-inflammation-and-fibrosis-5208p3icoz.pdf

Zhong-Xing Huang

Papers

GSDME-mediated pyroptosis promotes inflammation and fibrosis in obstructive nephropathy.