The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

Abstract

Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease. An increasing complement of non-canonical elements function as co-factors in TGF-β1 signaling. p53 is a particularly prominent transcriptional co-regulator of several TGF-β1 fibrotic-response genes by complexing with TGF-β1 receptor-activated SMADs. This cooperative p53/TGF-β1 genomic cluster includes genes involved in cellular proliferative control, survival, apoptosis, senescence, and ECM remodeling. While the molecular basis for this co-dependency remains to be determined, a subset of TGF-β1-regulated genes possess both p53- and SMAD-binding motifs. Increases in p53 expression and phosphorylation, moreover, are evident in various forms of renal injury as well as kidney allograft rejection. Targeted reduction of p53 levels by pharmacologic and genetic approaches attenuates expression of the involved genes and mitigates the fibrotic response confirming a key role for p53 in renal disorders. This review focuses on mechanisms underlying TGF-β1-induced renal fibrosis largely in the context of ureteral obstruction, which mimics the pathophysiology of pediatric unilateral ureteropelvic junction obstruction, and the role of p53 as a transcriptional regulator within the TGF-β1 repertoire of fibrosis-promoting genes.

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

“…TAZ is required for maximal TGF-β1-mediated expression of the SMAD target gene encoding plasminogen activator inhibitor-1 (PAI-1), a potent profibrotic clade E member of the serine protease inhibitor family (SERPINE1) [ 27 , 28 , 29 , 30 ], and a similar involvement of YAP in TGF-β1-induced PAI-1 expression is evident in lung tumor cells [ 31 ]. KEGG analysis confirmed, moreover, that convergence of the TGF-β and Hippo signaling pathways regulates transcription of the fibrosis-inducing connective tissue growth factor (CTGF; CCN2) and SERPINE1 genes [ 32 ] ( Figure 1 ). YAP knockdown effectively reduces levels of both CCN2 and PAI-1 (SERPINE1), while introduction of the constitutively active YAP S127A construct increases PAI-1 expression in immortalized cell lines [ 33 ].…”

“…Cytoscape profiling, moreover, similarly implicates SERPINE1 as a major core gene in the genomic program of tissue fibrosis, where it modulates focalized uPA/uPAR-dependent pericellular proteolysis and functions as a signaling activator for LRP1. String Protein– Protein Interaction Network and Gene Ontology analyses confirmed the cooperative role of SERPINE1 and TGF-β1 in the global process of normal and maladaptive (fibrotic) repair; both significantly contribute to the desmoplastic reaction and subsequent enhanced tissue stiffness [ 32 ]. This stromal barrier, and the associated increase in interstitial fluid, attenuates the effective delivery of chemotherapeutics to the TME (e.g., [ 7 , 191 ]).…”

Inflammation and fibrosis in the coal dust-exposed lung described by confocal Raman spectroscopy

“…These results were also consistent with the 1,080 cm −1 lipid band. p53 is a particularly prominent transcriptional coregulator of TGF-β1 fibrosis response genes ( Higgins et al, 2021 ). The expression of p53 was especially marked in the CWP-3M group ( Figs.…”

Butyrate Protects against Diet-Induced NASH and Liver Fibrosis and Suppresses Specific Non-Canonical TGF-β Signaling Pathways in Human Hepatic Stellate Cells

“…Suppression of YAP/TAZ activation by BU may be of particular importance because YAP/TAZ has been shown to sense ECM stiffness and to promote ECM production in a self-sustaining feedforward loop [ 34 ]. Interestingly, it was very recently shown that PAI-1 protein expression is mainly determined by the YAP/TAZ signaling pathway [ 35 ]. Therefore, the reduction of PAI-1 protein expression shown with butyrate in the present study confirms the predicted observed reduction in the Hippo signaling pathway (YAP/TAZ signaling) on the protein level.…”