Acute kidney injury and maladaptive tubular repair leading to renal fibrosis

Abstract

Purpose of review: Despite improvements in acute kidney injury (AKI) detection, therapeutic options to halt the progression of AKI to chronic kidney disease (CKD) remain limited. In this review, we focus on recent discoveries related to the pathophysiology of the AKI to CKD continuum, particularly involving the renal tubular epithelial cells, and also discuss related ongoing clinical trials. While our focus is on injured renal tubular epithelial cells as initiators of the cascade of events resulting in paracrine effects on other cells of the kidney, the summation of maladaptive responses from various kidney cell types ultimately leads to fibrosis and dysfunction characteristic of CKD.

Recent findings: Recent findings that we will focus on include, but are not limited to, characterizations of: the association between cell cycle arrest and cellular senescence in renal tubular epithelial cells and its contribution to renal fibrosis, chronic inflammation with persistent cytokine production and lymphocyte infiltration among unrepaired renal tubules, mitochondrial dysfunction and a unique role of cytosolic mitochondria DNA in fibrogenesis, prolyl hydroxylase domain proteins as potential therapeutic targets, and novel mechanisms involving the Hippo/yes-associated protein/transcriptional coactivator with PDZ-binding pathway.

Summary: Potential therapeutic options to address CKD progression will be informed by a better understanding of fibrogenic pathways. Recent advances suggest additional drug targets in the various pathways leading to fibrosis.

Scheme of novel pathways in AKI to CKD progression. (1) Cell cycle arrest and senescence: in overt renal tubular injuries, cellular senescence/TASCC formation is present in proximal tubular cells, resulting in a profibrotic cell cycle arrest at the G2/M phase. Deletion of DDR protein such as ATR in proximal tubules exacerbates maladaptive repair. (2) Inflammation: inflammatory responses after AKI upregulates cytokine/chemokine release including IL-1 and TNF-α, which subsequently activates downstream MyD88-mediated NF-κB production and necrosome formation. Complement activation, increased lymphangiogenesis and persistent infiltration of immune cells, also have been implicated in AKI to CKD transition. (3) Hypoxia: reduced O₂ delivery and vascular rarefaction contribute to hypoxia-mediated tubular injuries. Increased miR-493 is associated with G2/M arrest, and the deletion of FoxO3 leads to increased autophagy and oxidative stress. (4) Hippo/YAP/TAZ pathway: secretion of TGF-β after AKI increases the nuclear accumulation of TAZ, and activates myofibroblast in concert with CTGF, leading to maladaptive repair and interstitial fibrosis. (5) Mitochondrial dysfunction: dysregulated fatty acid oxidation (FAO) leads to reduced ATP generation and excessive oxidative stress. Lack of phosphorylated ACC increased malonyl-CoA formation, which inhibits free fatty acid utilization by blocking CPT1 transporter. Translocation of mtDNA during tubular injury triggers the STING pathway, enhancing cytokine production and inflammation. ATR, Ataxia Telangiectasia mutated and Rad3-related; TASCC, rapamycin (TOR)-autophagy spatial coupling compartment; RIPK1, receptor-interacting serine-threonine protein kinase; MLKL, mixed lineage kinase domain-like; STMN-1, Stathmin-1; TGF-β, transforming growth factor-beta; CTGF, connective tissue growth factor; YAP, yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding motif; ACC, acetyl-CoA carboxylase; CPT, carnitine palmitoyl transferase; STING, cGAS-stimulator of interferon genes.