Tiny sentinels: how cilia guard the kidneys in ischaemia–reperfusion injury

Renal ischaemia–reperfusion (IR) is a major cause of acute kidney injury (AKI), affecting a significant percentage of hospitalized patients and leading to high mortality rates and an increased risk of chronic kidney disease. Despite extensive research, effective pharmacological therapies for IR-induced AKI remain elusive. The study by Maknis et al. (2024) provides groundbreaking insights into a novel mechanism of renal protection through the preservation of primary cilia via angiotensin II type 2 receptor (AT2R) activation in a rat experimental model. Primary cilia are sensory organelles that play a critical role in maintaining cellular homeostasis in renal tubular cells (Bell et al., 2011). They are involved in sensing mechanical and chemical changes in the tubular environment and transducing these signals to regulate cellular processes such as proliferation, differentiation and apoptosis. The connection between ciliary dysfunction and renal pathologies became evident with the discovery that genes mutated in polycystic kidney disease (PKD) were associated with ciliary proteins, establishing primary cilia as central players in kidney health (Ma, 2021). Maknis et al. explore the protective effects of AT2R activation in the context of IR injury (IRI) using a rat experimental model. Their findings demonstrate that pretreatment with the AT2R agonist C21 significantly reduces tubular cell deciliation and maintains ciliary length in both cortical and medullary tubules during IR. This preservation of primary cilia correlates with improved tubular morphology and reduced kidney damage, highlighting a potential therapeutic target for IR-induced AKI. The protective effects of AT2R activation are mediated through several key mechanisms. (1) Prevention of primary cilia shortening and tubular cell deciliation: pretreatment with C21 significantly reduced the loss of primary cilia and maintained ciliary length in renal tubular cells subjected to IRI. This effect was more pronounced in cortical tubules. (2) Increased α-tubulin acetylation at the primary cilia: AT2R activation by C21 increased the acetylation of α-tubulin, a marker of ciliary stability, specifically at the primary cilia in tubular cells. This effect was consistent both in vivo (rat model) and in vitro (MDCK cell model). (3) ERK1/2 pathway inhibition: AT2R activation inhibited the ERK1/2 signalling pathway, which is known to contribute to renal damage during IR. The inhibition of ERK1/2 by AT2R agonists or by specific inhibitors of ERK1/2 phosphorylation correlated with increased α-tubulin acetylation and improved cilia stability. (4) HDAC6 inhibition as a potential therapeutic strategy: inhibition of HDAC6, a deacetylase for α-tubulin, with tubastatin A also preserved ciliary integrity and improved cell viability under IR conditions. This suggests that targeting HDAC6 could be a viable strategy to enhance ciliary stability and protect against renal IR injury. The concept of ciliotherapies, which involves targeting ciliary function and stability to treat diseases, is gaining traction across various fields, including oncology and nephrology (Carotenuto et al., 2023). The study by Maknis et al. introduces a novel aspect of ciliotherapies in the context of renal IRI. By preserving primary cilia through AT2R activation, this approach not only enhances renal recovery following IR but also opens new therapeutic avenues for other cilia-related diseases. One promising strategy to enhance ciliary axoneme acetylation is through the inhibition of HDAC6. HDAC6 inhibition has been shown to increase cilia stability and length, as well as improve cell viability under stress conditions. This suggests that combining AT2R agonists with HDAC6 inhibitors could potentially offer synergistic protective effects in renal IR and other ciliopathies. Interestingly, new small-molecule HDAC6 inhibitors are currently under several clinical trials mostly in the oncology field (Kaur et al., 2022). While the findings from Maknis et al. are compelling, it is important to note that all their observations are based on an animal model. Translating these findings to human patients requires cautious optimism. Primary cilia have been shown to play a critical role in various human kidney diseases, and their preservation could potentially mitigate damage in conditions such as AKI. However, further research is needed to validate these findings in human subjects and to understand the specific mechanisms by which AT2R activation influences ciliary function in human renal pathology. The authors highlight the translational potential of their findings, noting that the AT2R agonist C21 is currently undergoing clinical trials for other conditions, such as idiopathic pulmonary fibrosis and endothelial dysfunction in type 2 diabetes mellitus. These trials could provide valuable safety and efficacy data that might support future studies on the use of C21 in renal IRI and related pathologies. Their findings lay the foundation for further studies to test the preventive effects of C21 in other pathologies related to the loss of cilia integrity and to evaluate its potential use in humans for ameliorating IR-AKI. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. E.P.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. L.F.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. S.G.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. Supported by National Institutes of Health Grant R01DK132781 (to S.A.G.). 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