TGF-β1/p53 signaling in renal fibrogenesis

Abstract

Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population. Regardless of etiology (diabetes, hypertension, ischemia, acute injury, urologic obstruction), persistently elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling networks and disease progression. TGF-β1 is the principal driver of renal fibrogenesis, a dynamic pathophysiologic process that involves tubular cell injury/apoptosis, infiltration of inflammatory cells, interstitial fibroblast activation and excess extracellular matrix synthesis/deposition leading to impaired kidney function and, eventually, to chronic and end-stage disease. TGF-β1 activates the ALK5 type I receptor (which phosphorylates SMAD2/3) as well as non-canonical (e.g., src kinase, EGFR, JAK/STAT, p53) pathways that collectively drive the fibrotic genomic program. Such multiplexed signal integration has pathophysiological consequences. Indeed, TGF-β1 stimulates the activation and assembly of p53-SMAD3 complexes required for transcription of the renal fibrotic genes plasminogen activator inhibitor-1, connective tissue growth factor and TGF-β1. Tubular-specific ablation of p53 in mice or pifithrin-α-mediated inactivation of p53 prevents epithelial G/M arrest, reduces the secretion of fibrotic effectors and attenuates the transition from acute to chronic renal injury, further supporting the involvement of p53 in disease progression. This review focuses on the pathophysiology of TGF-β1-initiated renal fibrogenesis and the role of p53 as a regulator of profibrotic gene expression.

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

“…for p53 docking in a typical dimer-of-dimers configuration, are not separated by a nucleotide spacer (105,106). These data as well as the inclusion of PAI-1 as a member of the p53 target database, the topographic proximity of the p53 binding motifs to the transcription start site, the chromatin immunoprecipitation-confirmed p53 occupancy of the PAI-1 promoter, and the pharmacologic and genetic findings reviewed earlier (71,73) conclusively implicate p53 as a major cofactor in PAI-1 gene transcription.…”

“…USF2 occupancy of the PAI-1 promoter proximal E box 2 (PE2) region E box (CACGTG) site, which adjoins the 3 59 SMAD binding elements (SBEs) that mediate TGF-b1induced gene expression ( Fig. 6A), is essential for the growth state-dependent transcriptional activation of the PAI-1 gene (71,(122)(123)(124). USF1 and -2 involvement in PAI-1 gene control has significant implications regarding both renal fibrosis and p53 function (124)(125)(126)(127)(128)(129)(130).…”

“…The phosphorylation-dependent formation of transcriptionally active complexes between p-p53 and SMAD2 and 3 are involved in the expression of a subset of TGF-b1 target genes (e.g., Mix2, p21, PAI-1, and matrix metalloproteinase 2) (68,71,73,74,76,136) (Fig. 6B).…”

New insights into TGF-β/Smad signaling in tissue fibrosis

“…Excessive evidence demonstrated that fibrogenesis is associated with renin-angiotensin system, inflammation and oxidative stress, transforming growth factor β (TGF-β)/Smad signaling, Wnt/βcatenin signaling and lipid metabolism [1][2][3][4][5][6][7][8][9][10]. Among them, TGF-β/ Smad signaling plays an important role in fibrosis [1,[11][12][13][14]. Bona fide TGF-β is sequestered into the matrix in a latent state and must be activated before it can bind to its receptors.…”

“…This review focuses on the action mechanism of TGF-β/Smad signaling pathway and its therapeutic intervention. In addition, we also discuss the effects of other intracellular factors including tumor necrosis factor receptor-associated factor 6, TGF-β-activated kinase 1, mitogenactivated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), p53 and integrin on TGF-β/Smad signaling pathway [13,[20][21][22]].…”