Mitochondrial Signaling, the Mechanisms of AKI-to-CKD Transition and Potential Treatment Targets

Abstract

Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.

Keywords: AKI; AKT1; CKD; acute kidney injury; chronic kidney disease; mitochondria.

Figure 1

Standard perspectives on the pathophysiology in the progression from AKI to CKD: When the kidney encounters one or more precipitating factors of AKI, it can undergo repair, restoring normal or near-normal structure and function through ‘adaptive’ repair. However, maladaptive and incomplete repair can result in the development of fibrosis and, ultimately, chronic kidney disease. Figure created with biorender.com (accessed on 1 December 2023).

Figure 2

Molecular signaling in the repair/disease progression. In the early stages of ischemia-reperfusion injury (IRI), regenerating tubules release factors such as TGF-β and MCP-1, recruiting inflammatory cells and inducing cellular damage. MMP activity intensifies, leading to interstitial edema and diminished renal blood flow. Crucial signaling cascades, including WNT/β-catenin and PI3K/AKT, play key roles in the progression from AKI to CKD. WNT/β-catenin activation contributes to renal fibrotic lesions, while PI3K/AKT exhibits a potential protective role. However, inflammation, mitochondrial dysfunction, oxidative stress, and impaired nitric oxide production lead to proximal tubular cell (PTC) re-differentiation. Regenerated tubular cells transform pericytes into fibroblasts, contributing to abnormal fibroblast behavior. Diverse signaling pathways perpetuate fibroblast transformation, ultimately causing extensive kidney tissue damage. Figure created with biorender.com (accessed on 1 December 2023).

Figure 3

Intracellular signaling cascades orchestrating the transition from AKI to CKD: dysregulation of PGC1α, AMPK, SIRT3, and their downstream genes NRF1/NRF2 is evident in AKI. Proximal tubular cells (PTCs) are particularly affected by kidney hypoxia and mitochondrial dysfunction. Persistent TGF-β in the glomerulus induces the deposition of fibrogenic matrix proteins, leading to glomerulosclerosis. Consequently, tubulointerstitial hypoxia triggers fibrogenesis, elevating levels of α-SMA and collagen I. As the disease progresses, dysfunctional renal tubules intensify the profibrotic response, activating the secretion of TGF-β, potentially inducing the production of HIF. Figure created with biorender.com (accessed on 1 December 2023).

Figure 4

Key mitochondrial integrity control systems: the PINK1–Parkin pathway functions as a checkpoint, identifying dysfunctional mitochondria for removal. Activation of PGC1α, facilitated by AMPK and SIRT1 in response to the demand for new mitochondrial genesis, plays a crucial role. Additionally, mitochondrial AKT1 acts as a regulator in ATP production through complex V. Figure created with biorender.com (accessed on 1 December 2023).