JAK inhibition and progressive kidney disease

Abstract

Purpose of review: To review the role of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling in the progression of chronic kidney diseases.

Recent findings: The JAK-STAT pathway transmits signals from extracellular ligands, including many cytokines and chemokines. While these responses are best characterized in lymphoid cells, they also occur in kidney cells such as podocytes, mesangial cells, and tubular cells. JAK-STAT expression and signaling abnormalities occur in humans and animal models of different chronic kidney diseases. Enhanced expression and augmented activity of JAK1, JAK2, and STAT3 promote diabetic nephropathy and their inhibition appears to reduce the disease. Activation of JAK-STAT signaling in autosomal dominant polycystic kidney disease may play an important role in cyst growth. Activation of JAK-STAT signaling promotes HIV-associated nephropathy and may also participate in the tubular responses to chronic obstructive uropathy. On the basis of data from experimental models, inhibition of JAK-STAT signaling, via increased expression of the suppressors of cytokine signaling proteins or pharmacologic inhibition of JAK and STAT proteins, could play a therapeutic role in multiple chronic kidney diseases.

Summary: Activation of the JAK-STAT pathway appears to play a role in the progression of some chronic kidney diseases. More work is needed to determine the specific role the pathway plays in individual diseases.

Fig. 1. Schema of JAK-STAT3 activation in diabetic nephropathy

In diabetes, high glucose levels induce advanced glycation end-product (AGE) formation. Both high glucose and AGE stimulate growth factors and cytokine production in kidney cells. After binding to their receptors, cytokines activates JAKs which in turn lead to tyrosine phosphorylation of STAT3. Growth factors can activate tyrosine receptor kinases and Src family kinases which also induce tyrosine phosphorylation of STAT3. STAT3 is also phosphorylated at its serine site by MAPK to enhance its transcriptional activity. MAPK is activated in diabetes by either activation of the AGE receptor (RAGE) or by growth factors (EGF and TGF-β). Phosphorylated STAT3 then dimerizes and enters the nucleus to activate gene transcription. Recent data suggest that acetylation of STAT3 is also required for its activation. Acetylation of STAT3 is induced by ROS-mediated PCAF activation and is inhibited by SIRT1, a deacetylase. STAT3 mediates transcription activation of SOCS which in turn inhibits STAT3 activation, forming a negative feedback loop.