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

Abstract

Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF‐β1 levels result in the relentless progression of fibrotic disease. TGF‐β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF‐β1‐induced signaling pathway and a transcriptional coregulator of several TGF‐β1 profibrotic response genes by complexing with receptor‐activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53‐TGF‐β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor‐1 (PAI‐1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF‐β1‐responsive genes possess p53 binding motifs. p53 up‐regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin‐ and ischemia/reperfusion‐induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF‐β1 cluster with an emphasis on the potent fibrosis‐promoting PAI‐1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF‐β1‐p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications. FASEB J. 33, 10596–10606 (2019). http://www.fasebj.org

SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis

“…The mechanisms of kidney disease induced by hypertension are diverse and have not been fully understood. Hypertension leads to renal fibrosis, which might be via transforming growth factor-β1 (TGF-β1) and fibroblast-specific protein 1 (FSP-1) associated pathways [ 4 , 5 ]. In our previous study, we demonstrated that the production of TGF-β1 by pericytes and the pericyte–fibroblast transition contributed to renal fibrosis in the endothelial-specific prolyl hydroxylase domain protein-2 (PHD2) knockout mice [ 6 ].…”

Using Network Pharmacology to Explore the Mechanism of Peach Kernel-Safflower in the Treatment of Diabetic Nephropathy

“…Akt1 protein and mRNA are only slightly expressed in the kidney tissue of normal rats while in the kidney tissue of DN rats, the expression of Akt1 protein and mRNA is significantly increased [ 28 , 29 ]. Pharmacologic and genetic approaches targeting p53 attenuated expression of related genes and reduced the fibrosis response, confirming the involvement of p53 in renal disease [ 30 ].…”

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

“…The involvement of p53 in renal disease was initially defined in a rat model of ischemia-reperfusion injury (Kelly et al, 2003). p53 induction and increased p53 serine 15 phosphorylation is also evident in the kidney following nephrotoxin (e.g., cisplatin, aristolochic acid) administration or UUO, particularly in the dysmorphic epithelium (Zhou et al, 2010;Wei et al, 2007;Samarakoon et al, 2013a,b), and renal allograft rejection (Higgins et al, 2019). Recent studies, furthermore, link tubular epithelial dysfunction in response to both acute (e.g., ischemiareperfusion, nephrotoxins) and more protracted (UUO) injury to the progression of renal fibrosis via the p53 and JNK pathways with the retention of TGF-β signaling .…”

“…p53 is activated in the injured renal epithelium initiating cell cycle arrest at the G 1 and G 2 /M checkpoints depending on the participating effectors (e.g., ATM, ATR, CK1, CK2, p21, TGF-β1) and extent of tissue hypoxia (Thomasova and Anders, 2015;Tang et al, 2018Tang et al, , 2019Tang et al, , 2020Liu et al, 2019). TGF-β1 signaling in the damaged kidney increases p53 levels and phosphorylation, particularly at p53 S9/15 , promoting p53 stabilization and triggering p53-SMAD2/3 interactions resulting in transcription of the growth inhibitor p21 and subsequent p21-dependent G 1 arrest (Higgins et al, 2019). While p21 is a major p53 responsive gene, p53 upregulation in hypoxic tubular cells also suppresses CDK1, cyclin B 1 , and cyclin D 1 expression, potentially increasing residence time in G 2 /M.…”

“…siRNA-directed silencing of p53, moreover, mitigates the severity of cisplatin-and ischemic-induced kidney damage (Molitoris et al, 2009). Pharmacologic inhibition of p53 activation with pifithrin-α, delivery of p53 siRNA or genetic deletion of p53 in the proximal tubular epithelium attenuates both prolonged G 2 /M residence and the fibrotic response to cisplatin, UUO or ischemic injury (Wei et al, 2007;Ying et al, 2014;Tang et al, 2018;Higgins et al, 2019;Liu et al, 2019;Molitoris, 2019). Similarly, cisplatin-or bilateral ischemia-induced AKI in streptozotocin-treated mice or genetically susceptible (Akita) diabetic animals is significantly diminished by pifithrin-α, p53 siRNA or proximal tubule-targeted p53 ablation (Peng et al, 2015).…”