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.
Highlights
Basavarajappa, Beckman Research Institute of City of Hope, United States Padmanabhan Pattabiraman, Indiana University, Purdue University
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
ataxia telangiectasia and Rad3related serine/threonine-protein kinase (ATR) deletion in renal proximal tubular epithelial cells exacerbates maladaptive repair, increases the number of senescent cells and promotes expression of a profibrotic secretory phenotype (Kishi et al, 2019). These findings suggest that ATR provides a protective role in the injured proximal tubular epithelium to restrict or attenuate exuberant repair while highlighting the role of p53 in renal disease since treatment with the p53 inhibitor PIF-α significantly reduces the fraction of G2/M cells and mitigates the fibrotic response (Yang et al, 2010; Overstreet et al, 2014; Liu et al, 2019)
Summary
Acute kidney injury (AKI) and chronic kidney disease (CKD) comprise a rapidly growing medical and economic burden within the US as well as globally. Dot1lAC phenotypes were mitigated in the double-knockout DEAC mice with similar results evident in streptozotocin-induced diabetes and normal aging (Zhang et al, 2020) This is the first demonstration that loss of histone H3 K79 methyltransferase Dot1l promotes renal fibrosis due, in large measure, to endothelin-1 up-regulation in the collecting duct epithelium consistent with the implication that Dot1l exerts an antifibrotic function by repressing endothelin-1 transcription. Kidney fibrosis in response to UUO, is epigenetically regulated through Dot1l action in the connecting tubule and collecting duct It appears, that the pathophysiology of obstructive uropathy is both complex and likely involves the entire nephron. The growing appreciation for the extensive cross-talk and mutual inducibility between the TGF-β1 and endothelin-1 signaling systems in the kidney, their shared potent fibrogenic activities and ability to impact virtually all renal cell types (e.g., Eddy, 2000; Castañares et al, 2007; Dhaun et al, 2012; Wermuth et al, 2016) suggests that nephron segment-specific fibrotic factors may need to be considered in the formulation of targeted therapies
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