Systemic inflammation underlies septic pathophysiology and plays a central role in kidney injury. Sepsis is characterized by an excessive cytokine response (the so-called “cytokine storm”), activation of the innate immune system, and tissue infiltration by neutrophils and mononuclear cells. In the kidneys, this leads to endothelial damage and injury to tubular epithelial cells, disruption of the barrier function, and inflammatory edema.

It has been found that S-AKI involves an overproduction of pro-inflammatory cytokines (IL-6, IL-8, TNF-α, etc.), which contributes to damage of the nephrons. At the same time, sepsis also causes immune dysregulation—the initial hyperinflammatory phase can transition into immunoparalysis, which predisposes patients to secondary infections. In the context of the kidneys, an imbalance between pro- and anti-inflammatory signals disrupts homeostasis and triggers a cascade of injurious processes.

Apoptotic cell death of renal cells is a key mechanism of acute kidney injury in sepsis. The combination of ischemia (due to hypotension and reduced renal blood flow), inflammatory mediators, and the toxic effects of bacterial products (e.g., endotoxin) induces apoptosis of tubular epithelial cells. The early phase of S-AKI is associated with activation of apoptotic pathways through both the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) routes. The overproduction of calcium ions, inflammatory cascades, and the release of reactive oxygen species during sepsis can directly trigger apoptosis in renal cells.

Apoptosis results in the loss of functional nephrons, damage to tubules and glomeruli, and further deterioration of kidney function. Histological studies in sepsis models show apoptotic changes in the proximal tubules along with inflammatory infiltrates, confirming the significance of this mechanism.

Sepsis leads to abundant generation of reactive oxygen species (ROS) and reactive nitrogen species, resulting in oxidative stress in tissues. In the kidneys, activated neutrophils, macrophages, and dysfunctional mitochondria release large amounts of superoxide, peroxide, and other ROS. Excess free radicals directly damage cell membranes, proteins, and DNA, leading to lipid peroxidation, enzyme inactivation, and cell death.

Oxidative stress and inflammation reinforce each other—ROS activate pro-inflammatory signaling pathways, while inflammatory cells produce additional ROS, creating a vicious cycle. Consequently, the microvascular endothelium is damaged, and vascular permeability increases, contributing to tissue hypoxia. In septic kidney injury, levels of antioxidant enzymes (e.g., superoxide dismutase [SOD]) are observed to be reduced, whereas levels of malondialdehyde (MDA, a marker of lipid peroxidation) are elevated; these changes correlate with the severity of renal injury. This underscores the significance of the imbalance between pro-oxidant and antioxidant systems in the pathogenesis of S-AKI.

Microvascular disturbances in sepsis critically contribute to ischemic damage to the kidneys. Septic hypotension and vasodilation, despite being systemic, can result in inadequate perfusion of the renal cortex due to redistribution of blood flow and endothelial dysfunction. In the kidney’s microvasculature, inflammatory processes cause endothelial injury and trigger coagulation with the formation of microthrombi. These microthrombi, together with the broader disseminated intravascular coagulation (DIC), further reduce perfusion and lead to ischemia of nephrons.

Endothelial cells during sepsis express elevated levels of adhesion molecules, which facilitates the attachment of neutrophils and platelets to the vessel wall. The combination of reduced renal blood flow, microthrombosis, and increased vascular permeability leads to tissue edema and severe microcirculatory disturbances, exacerbating renal ischemia and injury. Microvascular dysfunction is closely intertwined with the other pathological mechanisms—inflammation and oxidative stress damage the endothelium, and ischemia-reperfusion events generate additional inflammatory and oxidative injuries.

In summary, S-AKI is a multifactorial condition: inflammatory hyperstimulation, cell apoptosis, oxidative stress, and microvascular disturbances act synergistically to damage the kidney tissue. The following sections examine how microRNAs influence these key pathogenetic factors, as well as their potential for diagnosis and therapy.

MicroRNA-155 is one of the most important pro-inflammatory microRNAs. During sepsis and S-AKI, miR-155 expression rises significantly, and high miR-155 levels are associated with more severe kidney injury. miR-155 suppresses negative regulators of inflammatory signaling (such as SOCS1), thereby promoting NF-κB activation and excessive cytokine production. It also exacerbates tubular cell apoptosis by targeting anti-apoptotic genes like Bcl-2 and SIRT1. In a mouse sepsis model, inhibiting miR-155 (via an antagomir) led to reduced TNF-α and IL-6 levels, increased SOCS1 expression, and significantly alleviated kidney injury. These findings indicate that miR-155 amplifies inflammation and apoptosis in S-AKI and that its suppression may be protective.^[5]

These miRNAs (from the same family) are induced as part of the negative feedback regulation of the TLR4/NF-κB pathway. They target key adaptor molecules like IRAK1 and TRAF6, thereby suppressing excessive inflammatory responses. In the context of septic kidney injury, high levels of miR-146 generally correlate with dampened inflammation. For instance, in kidney epithelial cells (HK-2), a miR-146b mimic suppresses NF-κB activation and reduces the production of inflammatory cytokines. In animal models, upregulating miR-146a has shown protective effects: in a septic kidney injury model, treatment with dexmedetomidine increased miR-146a expression, which in turn decreased oxidative stress and inflammation and improved renal function. Similarly, mesenchymal stem cell-derived exosomes enriched with miR-146b suppressed IRAK1 expression and significantly improved the survival of septic mice while protecting the kidneys. These findings underscore the anti-inflammatory, protective role of miR-146 in S-AKI.^[6]

This is one of the most studied microRNAs in kidney injury, but it shows contradictory effects in sepsis. On one hand, some studies indicate that overexpression of miR-21 during sepsis prolongs kidney dysfunction and exacerbates tubular cell apoptosis. Elevated kidney miR-21-3p caused cell cycle arrest (affecting the AKT/CDK2/FOXO1 pathway) and apoptosis progression in mice with LPS-induced AKI. On the other hand, several studies report a protective effect of miR-21: it has been shown that miR-21 can reduce apoptosis and inflammation by targeting PTEN (thus activating the AKT survival pathway) and PDCD4 (thereby suppressing NF-κB). For example, delivering an miR-21 mimic in a septic model resulted in lower levels of inflammatory cytokines and less structural damage to the kidney. Conversely, the absence of miR-21 has been linked to more severe injury in sepsis. These conflicting results suggest that the effect of miR-21 is context-dependent—different signaling pathways, cell types, or stages of injury might alter its function. Further research is needed to determine whether miR-21 exerts a net protective or harmful role in S-AKI.^[7,8]

Known as a “hypoxic” microRNA, its expression is driven by HIF-1 under low oxygen conditions. Sepsis often causes tissue hypoxia; accordingly, miR-210 is significantly elevated in S-AKI, both in kidney tissue and in the circulation. miR-210 is thought to participate in metabolic reprogramming toward anaerobic metabolism and adaptation to hypoxia. Clinically, plasma miR-210 levels correlate with the severity of acute injury—in a study of critically ill patients, plasma miR-210 was an independent predictor of survival in AKI. In another cohort of septic patients, miR-210 was among the most upregulated miRNAs in those who developed AKI, and the combined measurement of miR-210 with other markers achieved high sensitivity (~81%) and specificity (~81%) for early detection of S-AKI. These findings suggest that miR-210 not only reflects the hypoxia-driven pathophysiology and mitochondrial dysfunction but may also hold prognostic value in septic kidney injury.^[9]

MicroRNA-22-3p is an anti-inflammatory and cytoprotective microRNA that is decreased in septic AKI. Under normal conditions, miR-22-3p restrains inflammation and apoptosis by targeting factors such as HMGB1 (an alarmin that activates TLR4/NF-κB) and PTEN (a negative regulator of the AKT pathway). In a septic model, reduced miR-22-3p expression leads to hyperactivation of NF-κB inflammatory signaling and increased apoptosis, whereas delivery of a miR-22 mimic has the opposite effect—it inhibits PTEN, enhances pro-survival AKT/mTOR signaling, and lowers cytokine release. Clinical data support its importance: low serum and urinary miR-22-3p levels in septic patients are associated with higher AKI risk and lower 28-day survival. For this reason, miR-22-3p is considered a potential early warning and prognostic biomarker, as well as a possible therapeutic target—boosting its activity might protect the kidneys in sepsis.

MicroRNA-23a-3p is another protective microRNA, whose expression declines in S-AKI. Normally, miR-23a-3p helps maintain an anti-inflammatory balance: it suppresses the expression of the protein FKBP5 (a cofactor needed for full activation of glucocorticoid receptors and NF-κB), thus limiting the inflammatory response. It also targets Wnt5a, a component of the Wnt/β-catenin pathway associated with kidney injury and fibrosis. In vitro, LPS exposure was shown to reduce miR-23a-3p levels in renal epithelial cells, leading to increased FKBP5 expression, NF-κB activation, and release of IL-6 and IL-8. Overexpression of miR-23a-3p (or inhibition of FKBP5) suppressed this inflammatory response and decreased apoptosis. In a sepsis model, restoring miR-23a-3p reduced kidney damage, confirming that it exerts protective effects through broad anti-inflammatory actions.^[10]

An example of a microRNA that exacerbates injury through its effects on apoptosis. miR-16-5p is upregulated in septic AKI and contributes to the inflammatory response and cell death by targeting Bcl-2—a key anti-apoptotic protein. By suppressing Bcl-2, miR-16-5p lowers the threshold for apoptosis in tubular cells, leading to more pronounced LPS-induced inflammation and cell death. Blocking miR-16-5p (with an antagonist) produces the opposite effect: it restores Bcl-2 levels and limits inflammation, thereby protecting the cells. Similar outcomes have been observed with inhibition of other pro-apoptotic miRNAs like miR-543 and miR-34b-5p, which also target members of the Bcl-2 family or related molecules.^[11]

This is an interesting case of a microRNA that is induced by the inflammatory process itself and acts as an endogenous protective mechanism. In an in vivo sepsis model, miR-26a-5p levels rose in the kidneys in an NF-κB-dependent manner, and this miRNA targeted and suppressed IL-6 expression, thereby easing inflammation. miR-26a-5p also targets CHAC1 (a pro-oxidative factor) and reduces oxidative stress in damaged cells. Blocking exosome release (which retains more miR-26a-5p within cells) further enhanced this protective effect, resulting in lower inflammation and less fibrosis in a proteinuria model. Due to its multiple protective actions (anti-IL-6, anti-oxidative, anti-fibrotic), miR-26a-5p is a potential therapeutic target for bolstering endogenous defense mechanisms in S-AKI.

The pathogenesis of S-AKI involves a complex network of gene regulators, and many additional miRNAs are implicated in various aspects. For example, miR-106a (which is elevated in sepsis) promotes inflammation and apoptosis by targeting the anti-angiogenic factor THBS2 and likely contributes to endothelial dysfunction. miR-150-5p and miR-181a are involved in JAK/STAT signaling, and their downregulation in S-AKI is associated with increased oxidative stress. miR-128-3p has a dual effect—some studies identify it as pro-inflammatory (stimulating NF-κB and cytokine production), while others find it to be anti-inflammatory (when overexpressed, it suppresses the LPS response via TGFβR2). miR-132-3p protects against LPS-induced AKI in mice by reducing the expression of KIM-1 (HAVCR1), a marker of tubular injury. miR-21-5p (when secreted by endothelial progenitor cells in exosomes) improves the condition of the renal endothelium during sepsis by targeting the transcription factor RUNX1, thereby protecting the microcirculation and reducing capillary damage. This wide array of microRNAs and their targets (inflammatory mediators, pro- and anti-apoptotic proteins, antioxidant factors, signaling kinases, etc.) highlights the complexity of gene regulation in S-AKI. MicroRNAs form a regulatory network that largely determines whether certain pathological processes (such as inflammation or apoptosis) are amplified or suppressed. Understanding this network opens up opportunities for new diagnostic approaches (by monitoring miRNA profiles) and for therapeutic interventions (by targeting key microRNAs, as discussed below).