JAK/STAT signaling in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is the most important microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. The Janus kinase/signal transducer and activator of the transcription (JAK/STAT) signaling pathway, which is out of balance in the context of DKD, acts through a range of metabolism-related cytokines and hormones. JAK/STAT is the primary signaling node in the progression of DKD. The latest research on JAK/STAT signaling helps determine the role of this pathway in the factors associated with DKD progression. These factors include the renin–angiotensin system (RAS), fibrosis, immunity, inflammation, aging, autophagy, and EMT. This review epitomizes the progress in understanding the complicated explanation of the etiologies of DKD and the role of the JAK/STAT pathway in the progression of DKD and discusses whether it can be a potential target for treating DKD. It further summarizes the JAK/STAT inhibitors, natural products, and other drugs that are promising for treating DKD and discusses how these inhibitors can alleviate DKD to explore possible potential drugs that will contribute to formulating effective treatment strategies for DKD in the near future.

Pathomechanisms of Diabetic Kidney Disease

“…Recent studies focused on JAK/STAT signaling shed light on its involvement in various factors linked to the progression of DKD including fibrosis, immunity, inflammation, aging, autophagy, and EMT. Thus it stands as the central signaling hub in the advancement of DKD [243]. A direct relationship between tubulointerstitial JAK/STAT expression and progression of kidney failure in patients with DKD has been observed [244].…”

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation

“…RAGE, a crucial protein in cell signaling pathways, is involved in complex interactions with other cell surface receptors, playing a vital role in cellular responses and protein expression ( Figure 1 ). RAGE activation triggers major intracellular signaling pathways, including the Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway [ 14 ], Phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) pathway [ 15 ], Janus kinase (JAK)-signal transducer and activator of transcription (STAT) [ 16 ] pathway, etc. The processes behind RAGE activation are also influenced by its degree of activity.…”

“…RAGE binding with its ligand phosphorylates its downstream MAPK [ 17 ] and activates NF-κB protein and it translocate to the nucleus to stimulate the production of inflammatory mediators through transcription contributing to the amplification of inflammatory signaling. RAGE-mediated activation of PI3K/Akt can influence cell survival and cellular responses [ 16 , 18 ]. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway regulates cell proliferation, differentiation, and immune responses.…”

“…The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway regulates cell proliferation, differentiation, and immune responses. RAGE-induced activation of JAK/STAT may modulate cellular functions related to inflammation and tissue repair [ 16 ]. RAGE activation is associated with the generation of reactive oxygen species (ROS), which contribute to oxidative stress and cellular damage ( Figure 2 ).…”

Macrophage colony-stimulating factor and its role in the tumor microenvironment: novel therapeutic avenues and mechanistic insights

“…Phosphorylated STATs form homodimers or heterodimers that translocate to the cell nucleus, thereby controlling gene transcription and expression. This axis is a core intracellular signaling pathway that regulates various cytokine and growth factor signaling cascades, mediating downstream events such as inflammation infiltration, immune responses, repair, proliferation, differentiation, movement, and cell apoptosis (53).…”