PTEN in kidney diseases: a potential therapeutic target in preventing AKI-to-CKD transition

Abstract

Renal fibrosis, a critical factor in the development of chronic kidney disease (CKD), is predominantly initiated by acute kidney injury (AKI) and subsequent maladaptive repair resulting from pharmacological or pathological stimuli. Phosphatase and tensin homolog (PTEN), also known as phosphatase and tensin-associated phosphatase, plays a pivotal role in regulating the physiological behavior of renal tubular epithelial cells, glomeruli, and renal interstitial cells, thereby preserving the homeostasis of renal structure and function. It significantly impacts cell proliferation, apoptosis, fibrosis, and mitochondrial energy metabolism during AKI-to-CKD transition. Despite gradual elucidation of PTEN's involvement in various kidney injuries, its specific role in AKI and maladaptive repair after injury remains unclear. This review endeavors to delineate the multifaceted role of PTEN in renal pathology during AKI and CKD progression along with its underlying mechanisms, emphasizing its influence on oxidative stress, autophagy, non-coding RNA-mediated recruitment and activation of immune cells as well as renal fibrosis. Furthermore, we summarize prospective therapeutic targeting strategies for AKI and CKD-treatment related diseases through modulation of PTEN.

Keywords: AKI; AKI-to-CKD; CKD; PTEN; kidney.

Figure 1

The pathways and molecular mechanisms of PTEN in the progression of AKI. Various pharmacological or pathological factors including ischemia–reperfusion, cisplatin-induced nephrotoxicity, and sepsis, can induce alterations in the expression of SP1 transcription factor, non-coding RNA (ncRNA) molecules, and reactive oxygen species (ROS) within renal tubular epithelial cells. These changes subsequently modulate PTEN expression either positively or negatively. Consequently, the PI3K/AKT/mTOR cascade reaction is triggered and leads to downstream gene modifications associated with inflammation, autophagy, and oxidative stress. Ultimately, these detrimental effects contribute to renal tubular injury and exacerbates AKI. IRI, ischemia–reperfusion injury; Cisp, Cisplatin.

Figure 2

PTEN governs the process of renal adaptive and maladaptive repair in AKI-to-CKD transition. Upon the initiation of AKI, M1 macrophages undergo polarization to M2 phenotypes within the confines of immunoregulatory capacity, leading to the secretion of anti-inflammatory factors to facilitate adaptive kidney repair, thereby mitigating AKI. Conversely, the undue inhibition of PTEN promotes monocyte polarization toward M1 macrophages, suppresses PTEN expression, induces EMT, and enhances renal interstitial fibrosis. Simultaneously, reduced PTEN levels lead to decreased mitochondrial oxidative phosphorylation and mitochondrial membrane permeability, resulting in mitochondrial dysfunction and apoptosis via the caspase protein cascade. Moreover, severe AKI activates the β-catenin/Notch signaling axis to promote BMP-mediated repression of PTEN along with its receptor BMPR, while suppressing inflammatory responses triggered by the PI3K/AKT/mTOR pathway. The synergistic consequences of these effects severely undermine the kidneys’ capacity for effective adaptive restoration, eventually leading to the progression of CKD. ECM, extracellular matrix; EMT, epithelial-mesenchymal transition; AKI, acute kidney injury; CKD, chronic kidney disease.