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 G₂/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.

肾，肺，心脏和肝系统的纤维化疾病与明显的发病率和死亡率有关。然而，预防或减少器官衰竭进展的有效疗法仍然是主要的临床挑战。尤其是，慢性肾脏病构成了越来越大的医疗负担，影响了超过15％的美国人口。无论病因（糖尿病，高血压，局部缺血，急性损伤，泌尿系统梗阻）如何，持续升高的TGF-β1水平都与促纤维化信号网络的激活和疾病进展有因果关系。TGF-β1是肾纤维化的主要驱动力，肾纤维化是一种动态病理生理过程，涉及肾小管细胞损伤/凋亡，炎性细胞浸润，间质成纤维细胞活化和过量的细胞外基质合成/沉积导致肾功能受损，并最终导致慢性和终末期疾病。TGF-β1激活ALK5 I型受体（使SMAD2 / 3磷酸化）以及非规范性受体（例如，src激酶，EGFR，JAK / STAT，p53）途径共同驱动纤维化基因组程序。这样的多路信号整合具有病理生理学后果。实际上，TGF-β1刺激了肾纤维化基因纤溶酶原激活物抑制剂-1，结缔组织生长因子和TGF-β1转录所需的p53-SMAD3复合物的激活和组装。小鼠中p53的管状特异性消融或pifithrin-α介导的p53失活可防止上皮G ₂/ M阻滞可减少纤维化效应物的分泌并减弱从急性到慢性肾损伤的转变，从而进一步支持p53参与疾病进展。这篇综述着重于TGF-β1启动的肾纤维化的病理生理学以及p53作为促纤维化基因表达调节剂的作用。