Selective JNK3 Inhibition Ameliorates TGF- β -Mediated Glomerular Injury and Fibrosis in the Kidneys

JNK3 was upregulated in kidney cortex tissues from patients with CKD with severe albuminuria, as well as in a mouse model of glomerulosclerosis. Selective inhibition of JNK3 effectively attenuated TGF- β -mediated podocyte injury and adriamycin-induced glomerulosclerosis. JMH021, highly potent and selective JNK3 inhibitor, showed significant protective effects against albuminuria and fibrosis in kidneys without toxicity.

Noncanonical TGF- β signaling plays a critical role in the progression of CKD, but the pathologic contributions of its downstream mitogen-activated protein kinases signaling such as extracellular signal-regulated kinase, p38 α , and c-Jun N -terminal kinase (JNK) remain unclear. We investigated whether JNK3, a JNK isoform traditionally considered neuron-specific isoform, contributes to TGF- β -mediated glomerular fibrosis and injury.

JNK3 expression and function were examined using differentiated human podocytes, an adriamycin (ADR)-induced mouse model of glomerulosclerosis, and kidney cortex tissues from patients with CKD. Genetic and pharmacologic approaches were used to assess the role of JNK signaling in TGF- β -induced cellular responses and glomerular injury.

Kidney cortex tissues from patients with CKD with severe albuminuria and ADR-treated mice exhibited increased JNK3 expression and enhanced c-Jun phosphorylation, indicating activation of JNK signaling in association with glomerular injury. In human podocytes, genetic or pharmacologic inhibition of JNK suppressed TGF- β -induced activation of Smad2/3 and extracellular signal-regulated kinase signaling, reduced endogenous TGF- β expression, and attenuated profibrotic phenotype changes. JNK inhibition also decreased reactive oxygen species production, preserved expression of podocyte structural proteins, including synaptopodin, podocin, and nephrin, and reduced albumin permeability. Among JNK isoforms, JNK3 knockdown conferred the greatest protection against TGF- β -induced loss of epithelial phenotype and fibrotic responses. We used JMH021, a selective imidazole-based JNK3 inhibitor, which more effectively prevented TGF- β -induced fibrosis and disruption of podocyte barrier function than the pan-JNK inhibitor SP600125. In vivo , JMH021 significantly improved ADR-induced glomerulosclerosis, foot process effacement, albuminuria, and kidney dysfunction, while avoiding the hepatotoxicity observed with SP600125.

These findings suggest that selective JNK3 inhibition effectively attenuates TGF- β -driven glomerular fibrosis and proteinuria without serious complications.