Tubular Cell Cycle Response upon AKI: Revising Old and New Paradigms to Identify Novel Targets for CKD Prevention

Abstract

Acute kidney injury (AKI) is characterized by a rapid deterioration of kidney function, representing a global healthcare concern. In addition, AKI survivors frequently develop chronic kidney disease (CKD), contributing to a substantial proportion of disease burden globally. Yet, over the past 30 years, the burden of CKD has not declined to the same extent as many other important non-communicable diseases, implying a substantial deficit in the understanding of the disease progression. The assumption that the kidney response to AKI is based on a high proliferative potential of proximal tubular cells (PTC) caused a critical confounding factor, which has led to a limited development of strategies to prevent AKI and halt progression toward CKD. In this review, we discuss the latest findings on multiple mechanisms of response related to cell cycle behavior of PTC upon AKI, with a specific focus on their biological relevance. Collectively, we aim to (1) provide a new perspective on interpreting cell cycle progression of PTC in response to damage and (2) discuss how this knowledge can be used to choose the right therapeutic window of treatment for preserving kidney function while avoiding CKD progression.

Keywords: acute kidney injury; alternative cell cycle; cell cycle arrest; chronic kidney disease; fibrosis; mitotic cell cycle; polyploidy; senescence.

Figure 1

Distinct cell cycle programming triggered in PTC upon acute injury. The scheme depicts the different possible fates of cell cycle programming in PTC after AKI. The mitotic cell cycle (light blue line) progressing through G1, S, G2, and M phases generates two daughter cells. Cell cycle arrest (red line with stop sign) of PTC at G1 and G2 checkpoints triggers a senescent/fibrotic phenotype. Alternative cell cycle (i.e., endoreplication) generates mono/multinuclear polyploid cells via endomitosis (yellow line) or mononuclear polyploid cells via endocycle (red line).

Figure 2

Old and new strategies employed to study cell cycle behavior of PTC after acute injury. PTC respond to acute injury by triggering different strategies: mitotic cell cycle, cell cycle arrest and alternative cell cycle. Use of cell cycle markers (A) and DNA content analysis (B) (light blue box; old strategies) cannot distinguish among the proliferating PTC (generated by “traditional” mitotic cell cycle) and the arrested PTC or the polyploid PTC (generated by alternative cell cycle). Recently, sophisticated strategies (light yellow box, new strategies) are now being employed to detect proliferating PTC, completing a mitotic cell cycle versus polyploid PTC generated by endoreplication. (C) The FUCCI2aR technology coupled with the measurement of the DNA content, can discern between PTC (diploids in G2/M), which express the mVenus protein (green cells), from polyploid PTC having a DNA content ≥ 4C, which express mCherry protein (red cells). However, this technology does not allow to discriminate proliferating PTC from arrested PTC because they are both diploids in G2/M expressing mVenus protein (green cells). (D) Innovative application of the Confetti reporter allows the recognition of diploid PTC, which express only one color (YFP, RFP, CFP, and GFP) of the reporter cassette from polyploid PTC, which express two or more combinations of color in the same cell (RFP-CFP, RFP-YFP, YFP-CFP, GFP-RFP, GFP-CFP, and GFP-YFP). This technology, however, does not allow the identification of arrested cells.

Figure 3

Windows of opportunity for potential druggable targets to treat AKI and avoid CKD progression. (A) Early treatment after AKI with HDAC inhibitors enhance kidney regeneration (green line) by promoting RPC proliferation. Conversely, early treatment with drugs that inhibit cell cycle arrest and/or polyploidization (p21, p53, and YAP1 inhibitors) increase mortality of mice and lead to CKD (red line). (B) Late treatment, after the acute phase of damage, with drugs that inhibit cell cycle arrest and/or polyploidization (p21, p53, HDAC, and YAP1 inhibitors) ameliorates kidney function and prevents fibrosis and senescence (green line). GFR: glomerular filtration rate.