Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming

Abstract

While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)–induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/flox and Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule–specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis

“…Excessive lipid accumulation and impaired FAO have been repeatedly observed in several animal models of acute and chronic renal injury, as well as in human patients (10,11,13,47,48). Increased lipid accumulation induces cellular lipotoxicity, contributing to fibrosis development (11).…”

“…A decrease in the expression of key metabolic transcription factors (PPARGC1A, PPARA, and PPARG) in tubule cells (15) has been associated with the progression of fibrosis and CKD. Transgenic expression of PPARGC1A and PPARA caused protection from acute kidney injury or kidney fibrosis, indicating the key role of metabolic pathways in maintaining kidney function and tubule health (10,13,51,52). Furthermore, age-associated impairment of PPARα and FAO aggravates renal fibrosis (53).…”

“…More recently, abnormal renal lipid accumulation has been linked to the development of CKD and renal fibrosis (8). This has led to the prevailing concept that tubulo-interstitial fibrosis can be mediated or perpetuated by metabolic alterations, whereby reduced fatty acid oxidation (FAO) plays a central role in promoting and prolonging fibrotic responses (9)(10)(11)(12)(13). The use of different models of chronic kidney injury leading to renal fibrosis, including unilateral ureteral obstruction (UUO), folic acid-induced nephropathy (FAN), ischemia/reperfusion, or genetically modified models, has allowed researchers to establish that this reduction is associated with decreased expression of numerous FAO-related genes in renal tubular epithelial cells (TECs).…”

De-Glycyrrhizinated Licorice Extract Attenuates High Glucose-Stimulated Renal Tubular Epithelial–Mesenchymal Transition via Suppressing the Notch2 Signaling Pathway

“…Although previous studies have shown that Notch1 expression in renal tubules correlated with tubulointerstitial fibrosis and decreased kidney function in patients with chronic kidney disease [15,16], the role of Notch1 in renal tubular epithelial de-differentiation (or EMT) and in tubulointerstitial fibrosis still remains controversial. Particularly, a more recent study from Huang et al [30] pointed out that the expression levels of Notch2 and its ligand Jagged-1 substantially correlated with the degree of interstitial fibrosis in several different kidney fibrosis models including folic acid (FA)-induced nephropathy, unilateral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease. Furthermore, they found that mice with tubule-specific genetic deletion of Notch2, but not Notch1, conferred protection against FA-induced kidney fibrosis [30].…”

“…Particularly, a more recent study from Huang et al [30] pointed out that the expression levels of Notch2 and its ligand Jagged-1 substantially correlated with the degree of interstitial fibrosis in several different kidney fibrosis models including folic acid (FA)-induced nephropathy, unilateral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease. Furthermore, they found that mice with tubule-specific genetic deletion of Notch2, but not Notch1, conferred protection against FA-induced kidney fibrosis [30]. Consistent with the findings from Huang et al [30], our data clearly demonstrated that activated Notch2, but not Notch1, was associated with EMT induction in HG-cultured NRK-52E cells (Figures 1 and 6).…”