The JNK-associated leucine zipper protein exerts a protective effect on renal parenchymal injury by limiting the inflammatory secretome in tubular cells.

JNK-associated leucine zipper protein (JLP) is a newly identified renal endogenous anti-fibrotic factor that is selectively enriched in renal tubular epithelial cells (TECs). The loss of JLP by TECs is a landmark event that heralds the progression of kidney fibrosis. JLP deficiency ensues a series of pathogenetic cellular processes that are conducive to fibrotic injury. Inflammatory injury is functionally relevant in fibrotic kidneys, and TECs play an essential role in fueling inflammation through aberrant secretions. It is speculated that the loss of JLP in TECs is associated with the relentless inflammation during the development of kidney fibrosis. This study examined the alteration of a panel of inflammatory signatures in TECs under kidney fibrotic circumstances using a Jlp gene-modified unilateral ureteral obstruction (UUO) mouse model or cultured HK-2 cells. It was found that a deficiency of JLP in TECs led to a significant increase in the secretion of inflammatory cytokines including interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and monocyte chemotactic protein-1 (MCP-1), overactivation of the nuclear factor (NF)-κB/c-Jun N-terminal kinase (JNK) pathway, as well as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis in response to pro-fibrotic damage. Additionally, the absence of JLP resulted in enhanced macrophage migration and fibroblast activation as paracrine effects elicited by injured TECs. In conclusion, the loss of JLP in TECs catalyses inflammatory injuries in the development of kidney fibrosis.