Notch‐3 receptor activation drives inflammation and fibrosis following tubulointerstitial kidney injury

Abstract

Kidney diseases impart a vast burden on affected individuals and the overall health care system. Progressive loss of renal parenchymal cells and functional decline following injury are often observed. Notch-1 and -2 receptors are crucially involved in nephron development and contribute to inflammatory kidney diseases. We specifically determined the participation of receptor Notch-3 following tubulointerstitial injury and in inflammatory responses. Here we show by heat map analyses that Notch-3 transcripts are up-regulated in human kidney diseases. A similar response was corroborated with kidney cells following TGF-β exposure in vitro. The murine unilateral ureteral obstruction (UUO) model mirrors hallmarks of tubulointerstitial injury and damage. A subset of tubular and interstitial cells demonstrated up-regulated Notch-3 receptor expression in diseased animals. We hypothesized a relevance of Notch-3 receptors for the chemotactic response. To address this question, animals with genetic ablation of receptor Notch-3 were analysed following UUO. As a result, we found that Notch-3-deficient animals are protected from tubular injury and cell loss with significantly reduced interstitial collagen deposition. Monocytic cell infiltration was significantly reduced and retarded, likely due to abrogated chemokine synthesis. A cell model was set up that mimics enhanced receptor Notch-3 expression and activation. Here a pro-mitogenic response was seen with activated signalling in tubular cells and fibroblasts. In conclusion, Notch-3 receptor fulfils non-redundant roles in the inflamed kidney that may not be replaced by other Notch receptor family members. Thus, specific blockade of this receptor may be suitable as therapeutic option to delay progression of kidney disease.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

“…25 We recently showed that Notch3-HeyL pathway activation promotes tubulointerstitial fibrosis and inflammation by increasing MCP-1 synthesis in the UUO model. 11 These findings suggest that activation of the Notch3-HeyL pathway can be a common renal pathogenic mechanism promoting glomerulosclerosis, tubulointerstitial fibrosis, and renal inflammation. It was also recently shown that the inhibition of HeyL induces the decrease of proinflammatory cytokines in breast cancer cells.…”

“…A similar interaction between inflammation and Notch3 neoexpression was also observed in renal tubular epithelial cells in our previous study using the unilateral ureteral obstruction (UUO) model, a classic model of tubular inflammation. 11 Recent studies observed an interaction between Notch3 and p65/NF-kB to regulate T cell function under control conditions or in disease. 23,24 A pathogenic role for the Notch3 receptor was first described in CADASIL syndrome.…”

“…Initially, the KO animals were provided by Dr. Anne Joutel in a B6/C57 background. 10,11 These animals were backcrossed 10 times in a Sv129 background in our animal facility. Decomplemented NTS was prepared as previously described.…”

“…10 In subsequent studies, we showed that Notch3 is induced in renal tubular epithelial cells subjected to ureteral obstruction and promotes renal inflammation and fibrosis. 11 In this study, we examined the role of Notch3 in a model of rapidly progressive renal disease and found that activation of Notch3 in podocytes induces phenotypic changes associated with cell migration, inflammation, proteinuria, and renal function loss. Inversely, mice lacking Notch3 expression were protected from the decline of renal function.…”

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression

“…40,41 Physical contact between cells induces the Notch signaling pathway. In liver sinusoids, KCs, LSECs, HSCs, lymphocytes, and hepatocytes contact each other and have a capacity to induce DLL4 expression in some disease setting.…”