The Role of Tβ4-POP-Ac-SDKP Axis in Organ Fibrosis

Abstract

Fibrosis is a pathological process in which parenchymal cells are necrotic and excess extracellular matrix (ECM) is accumulated due to dysregulation of tissue injury repair. Thymosin β4 (Tβ4) is a 43 amino acid multifunctional polypeptide that is involved in wound healing. Prolyl oligopeptidase (POP) is the main enzyme that hydrolyzes Tβ4 to produce its derivative N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) which is found to play a role in the regulation of fibrosis. Accumulating evidence suggests that the Tβ4-POP-Ac-SDKP axis widely exists in various tissues and organs including the liver, kidney, heart, and lung, and participates in the process of fibrogenesis. Herein, we aim to elucidate the role of Tβ4-POP-Ac-SDKP axis in hepatic fibrosis, renal fibrosis, cardiac fibrosis, and pulmonary fibrosis, as well as the underlying mechanisms. Based on this, we attempted to provide novel therapeutic strategies for the regulation of tissue damage repair and anti-fibrosis therapy. The Tβ4-POP-Ac-SDKP axis exerts protective effects against organ fibrosis. It is promising that appropriate dosing regimens that rely on this axis could serve as a new therapeutic strategy for alleviating organ fibrosis in the early and late stages.

The Pathophysiological Role of Thymosin β4 in the Kidney Glomerulus

“…The protective effect of Tβ4 on podocytes may also be mediated by its metabolite, the tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is generated by successive cleavage of Tβ4 by the enzymes meprin-α [51] and prolyl oligopeptidase (POP) [52] and is degraded by the angiotensin-I-converting enzyme [53]. AcSDKP has shown beneficial effects in a number of experimental models of kidney disease, most prominently showing anti-inflammatory and anti-fibrotic properties [54,55]. AcSDKP administration also improves albuminuria in murine models of hypertensive nephropathy [56][57][58], lupus nephritis [59,60], and nephrotoxic nephritis [61], suggesting that it protects the glomerular filtration barrier.…”

“…In this section, we discuss the effects of Tβ4 on macrophage infiltration in the context of glomerular disease. The anti-inflammatory role of Tβ4 and AcSDKP in kidney disease that primarily targets the tubulointerstitium have been reviewed previously [54,55,92,93].…”

“…In addition, Tβ4 metabolites may also play a role. Tβ4 sulfoxide disperses macrophages at the site of injury [95], and AcSDKP has anti-inflammatory and anti-fibrotic function in the kidney [54,55,92,93]. The inflammatory response has been associated with increased fibrosis in the kidney [96], and therefore the anti-fibrotic effects of Tβ4 in glomerular disease may be a downstream effect of its anti-inflammatory function.…”