Glomerular and tubular induction of the transcription factor c‐Jun in human renal disease

Abstract

The transcription factor c-Jun regulates the expression of genes involved in proliferation and inflammation in many cell types but its role in human renal disease is largely unclear. In the current study we investigated whether c-Jun activation is associated with human renal disease and if c-Jun activation regulates pro-inflammatory and pro-fibrotic genes in renal cells. Activation of c-Jun was quantified by scoring renal expression of phosphorylated c-Jun (pc-Jun) in control human renal tissue and in biopsies from patients with various renal diseases (diabetic nephropathy, focal glomerulosclerosis, hypertension, IgA nephropathy, membranous glomerulopathy, minimal change disease, membranoproliferative glomerulonephritis, systemic lupus erythematosus, acute rejection, and Wegener's granulomatosis); this was correlated with parameters of renal damage. Furthermore, we studied the functional role of c-Jun activation in human tubular epithelial cells (HK-2) stimulated with TGF-beta. Activated c-Jun was present in nuclei of glomerular and tubular cells in all human renal diseases, but only sporadically in controls. Across the diseases, the extent of pc-Jun expression correlated with the degree of focal glomerulosclerosis, interstitial fibrosis, cell proliferation, kidney injury molecule-1 (Kim-1) expression, macrophage accumulation, and impairment of renal function. In HK-2 cells, TGF-beta induced c-Jun activation after 1 h (+40%, p < 0.001) and 24 h (+160%, p < 0.001). The specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 abolished c-Jun phosphorylation at all time points and blunted TGF-beta- or BSA-induced procollagen-1alpha 1 and MCP-1 gene expression in HK-2 cells. We conclude that in human renal disease, the transcription factor c-Jun is activated in glomerular and tubular cells. Activation of c-Jun may be involved in the regulation of inflammation and/or fibrosis in human renal disease.

The role of stress-activated protein kinase signaling in renal pathophysiology

“…p-c-Jun staining was evident in many glomerular and tubular cells. Indeed, the number of p-c-Jun+ glomerular cells correlated with the degree of glomerulosclerosis, while tubulointerstitial p-cJun staining correlated with interstitial fibrosis and renal dysfunction, implicating JNK signaling in the pathogenesis of different forms of human kidney disease (23).…”

“…Immunostaining for phosphorylated-c-Jun, a well-defined marker of JNK signaling, identified a striking increase in JNK activation in kidney diseases including various glomerulonephritis, hypertension and diabetic nephropathy (23). p-c-Jun staining was evident in many glomerular and tubular cells.…”

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

“…20,21 These ROS can further promote mitochondrial fission 22 and abnormal signal transduction pathways. [23][24][25] A large number of studies have shown that mitochondrial dysfunction plays an important role in the progression of renal disease including renal tubular injury, chronic kidney disease, and acute renal failure, which can lead to renal disease aggravation and progression. [26][27][28] More and more evidences suggested that the damage of mitochondrial morphological and function plays an important role in the development of DN.…”

c-Jun NH2-Terminal Kinase Is Crucially Involved in Renal Tubulo-Interstitial Inflammation

“…It is important to note that overexpression of c-Jun, a major transcription factor downstream of JNK, induces MCP-1 in endothelial cells (Wang et al, 1999). We recently demonstrated that c-Jun inhibition decreases MCP-1 gene expression in human tubular epithelial cells (de Borst et al, 2007a). Conversely, dominant-negative c-Jun gene therapy reduced myocardial MCP-1 expression in a model of cardiac hypertrophy (Kim-Mitsuyama et al, 2006).…”