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Review
. 2018 May;27(5):739-753.
doi: 10.1177/0963689717743512. Epub 2018 Apr 27.

Acute Kidney Injury as a Condition of Renal Senescence

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Free PMC article
Review

Acute Kidney Injury as a Condition of Renal Senescence

Lucia Andrade et al. Cell Transplant. .
Free PMC article

Abstract

Acute kidney injury (AKI), characterized by a sharp drop in glomerular filtration, continues to be a significant health burden because it is associated with high initial mortality, morbidity, and substantial health-care costs. There is a strong connection between AKI and mechanisms of senescence activation. After ischemic or nephrotoxic insults, a wide range of pathophysiological events occur. Renal tubular cell injury is characterized by cell membrane damage, cytoskeleton disruption, and DNA degradation, leading to tubular cell death by necrosis and apoptosis. The senescence mechanism involves interstitial fibrosis, tubular atrophy, and capillary rarefaction, all of which impede the morphological and functional recovery of the kidneys, suggesting a strong link between AKI and the progression of chronic kidney disease. During abnormal kidney repair, tubular epithelial cells can assume a senescence-like phenotype. Cellular senescence can occur as a result of cell cycle arrest due to increased expression of cyclin kinase inhibitors (mainly p21), downregulation of Klotho expression, and telomere shortening. In AKI, cellular senescence is aggravated by other factors including oxidative stress and autophagy. Given this scenario, the main question is whether AKI can be repaired and how to avoid the senescence process. Stem cells might constitute a new therapeutic approach. Mesenchymal stem cells (MSCs) can ameliorate kidney injury through angiogenesis, immunomodulation, and fibrosis pathway blockade, as well as through antiapoptotic and promitotic processes. Young umbilical cord-derived MSCs are better at increasing Klotho levels, and thus protecting tissues from senescence, than are adipose-derived MSCs. Umbilical cord-derived MSCs improve glomerular filtration and tubular function to a greater degree than do those obtained from adult tissue. Although senescence-related proteins and microRNA are upregulated in AKI, they can be downregulated by treatment with umbilical cord-derived MSCs. In summary, stem cells derived from young tissues, such as umbilical cord-derived MSCs, could slow the post-AKI senescence process.

Keywords: Klotho; acute kidney injury; cell cycle arrest; mesenchymal stromal cells; oxidative stress; telomeres.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Fig. 1.
Fig. 1.
Mechanism of cell cycle arrest induced fibrosis. In addition to the quiescent state (G0), the cell cycle includes 4 tightly controlled phases: G1, S (DNA synthesis), G2, and M (mitosis). Cyclin D and cyclin E are cell cycle regulatory proteins synthesized in the G1 phase (in its early and late portions, respectively) but degraded when the cells enter the S phase. Cyclin B is required for progression from G2 to M, and an increased cyclin B/cyclin D ratio might represent accumulation of cells in G2/M, which can occur in maladaptative repair. The p16INK4a and p21Waf1/Cip1 proteins bind to cyclin-dependent kinase–cyclin heterodimers, causing cell cycle arrest in the G0 to G1 phase, inhibiting cell proliferation. Hypoxia and reactive oxygen species may activate protein kinases Chk1 and Chk2 through ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-related protein kinase signaling pathway, promoting cell cycle arrest in G2/M checkpoint. An excess of G2/M-arrested cells activates the Jun N-terminal kinase pathway, increasing levels of the transcription factor c-jun, which upregulates profibrotic cytokine production.
Fig. 2.
Fig. 2.
Main functions of the Klotho protein. Membrane Klotho is a 135-kDa transmembrane protein that interacts with the fibroblast growth factor receptor (FGF-R) as a co-receptor for FGF-23, regulating renal phosphate excretion and metabolism. Once cleaved by α-secretases, membrane Klotho becomes a soluble, 130-kDa peptide that is released from the cell surface, subsequently entering the bloodstream and the urine. At these sites, 130-kDa Klotho can undergo further cleavage by β-secretases, producing 65-kDa soluble peptides. Alternative splicing of the Klotho gene also creates a 65-kDa soluble Klotho, known as “secreted Klotho,” which is released into the bloodstream and urine with no need for enzymatic cleavages. All forms of soluble Klotho develop paracrine and systemic functions: In the distal nephron, soluble Klotho activates the transient receptor potential cation channel subfamily V (TRPV) calcium channels TRPV5 and TRPV6, increasing calcium reabsorption, and the renal outer medullary 1 potassium channel, increasing potassium secretion. In addition, Klotho inhibits Wnt signaling activity, thus contributing to the blocking of fibrogenic mechanisms. Klotho protein also regulates the oxidative stress through insulin growth factor 1 (IGF-1) signaling. Inhibition of IGF-1 permits forkhead box O3 action, elevating levels of the antioxidant enzymes manganese superoxide dismutase and catalase.

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