New Therapies For Acute Kidney Injury Show Promise

3 months ago

Acute kidney wounded (AKI) is simply a terrible renal upset affecting astir 10%-15% of hospitalized patients and up to 50% successful intensive attraction units (ICUs). Its pathogenesis involves analyzable inflammatory regulatory mechanisms. As halfway components of nan cytokine network, interleukins (ILs) exert pleiotropic effects successful AKI development, extensively participating successful inflammation, fibrosis, insubstantial wounded repair, and distant organ damage.

During AKI progression, chopped IL members execute divers biologic effects done unsocial signaling pathways. Pro-inflammatory ILs specified arsenic IL-1α, IL-1β, IL-12, IL-17A, and IL-18 exacerbate AKI, while protective ILs including IL-2, IL-10, IL-13, IL-27, and IL-37 mitigate injury. Certain ILs, specified arsenic IL-4, IL-6, IL-9, IL-11, IL-22, and IL-33, grounds dual roles.

Emerging therapeutic strategies targeting ILs aliases their receptors—particularly monoclonal antibodies and extracellular vesicle technology—show important promise. Consequently, knowing these mechanisms is captious for processing innovative therapies and improving outcomes successful AKI patients.

Origins and building of interleukins (ILs)‌

The interleukin (ILs) family is chiefly produced by T cells, B cells, macrophages, dendritic cells, endothelial cells, and epithelial cells. Most ILs are mini polypeptides aliases glycoproteins pinch molecular weights ranging from ‌15-30 kDa‌‌. Although amino acerb sequences alteration importantly crossed different ILs, members wrong nan aforesaid family often grounds ‌conserved series regions. Critically, nan building of ILs is intrinsically linked to their function-their unsocial ‌spatial conformation‌ and ‌structural domains‌ empower them to execute divers biologic roles wrong nan immune strategy (Figure 1)‌.

‌Mechanisms of ILs successful AKI‌

Mechanisms underlying nan exacerbation of AKI progression. IL-1α and IL-1β exacerbate inflammation and insubstantial harm successful divers AKI models (e.g., cisplatin-induced, ischemic) by activating nan ‌nuclear facet κB (NF-κB) pathway.IL-8 (CXCL8) recruits neutrophils done ‌CXCR1/2 receptors‌, promoting inflammatory responses, tubular compartment damage, senescence, and fibrosis‌.

Elevated plasma IL-8 levels service arsenic a biomarker for predicting terrible AKI‌.IL-12 aggravates AKI by enhancing ‌dendritic compartment maturation‌ and amplifying nan merchandise of aggregate inflammatory mediators‌.IL-17A worsens wounded successful sepsis-associated and cisplatin-induced AKI by expanding pro-inflammatory cytokines, inducing ‌neutrophil infiltration‌, and triggering tubular compartment apoptosis‌.

It further promotes consequent renal fibrosis‌.IL-18 is importantly elevated successful nan urine of AKI patients, serving arsenic a reliable early biomarker‌. It exacerbates sepsis-, nephrotoxic-, and ischemia-reperfusion-induced AKI by amplifying ‌inflammatory cascades‌‌.IL-36α contributes to AKI pathogenesis done NF-κB pathway activation and upregulation of IL-6/TNF-α (Figure 2)‌.

Mechanisms underlying nan inhibition of AKI progression. Low-dose IL-2 protects against ischemia-reperfusion-induced renal damage. Treatment pinch ‌IL-2/anti-IL-2 antibody complexes (IL-2C)‌ aliases ‌IL-2/IL-33 fusion macromolecule (IL-233)‌ importantly attenuates ischemia-reperfusion wounded (IRI) and nephrotoxic AKI, improving renal usability while reducing cellular apoptosis and oxidative stress.

IL-10 mediates anti-inflammatory and immunomodulatory responses done ‌JAK/STAT pathway activation‌.IL-15 enhances endurance signaling successful renal tubular epithelial cells via ‌JAK/STAT and PI3K/Akt pathways‌, mitigating cisplatin-induced apoptosis.

The nephroprotective effect of IL-17E (IL-25) involves ‌enhanced type 2 innate lymphoid compartment (ILC2s) activity‌, promotion of M2 macrophage polarization, and suppression of M1 macrophages.Additionally, IL-13, IL-27, IL-35, IL-37, and IL-38 show anti-inflammatory imaginable and renal protective properties (Figure 3).

The dual mechanisms of action of ILs successful AKI. IL-4 chiefly exerts biologic effects done activation of ‌JAK-STAT and PI3K/Akt/mTOR pathways‌. It facilitates ‌M2 macrophage polarization‌ to accelerate renal tubular repair, demonstrating protective effects successful IRI-AKI models, yet concurrently drives renal fibrotic progression.IL-6 activates ‌STAT3 via classical and trans-signaling pathways‌, participating successful anti-inflammatory responses.

Paradoxically, IL-6 deficiency improves renal usability and reduces inflammatory infiltration successful some IRI and HgCl2-induced AKI models, indicating its pro-inflammatory domiciled successful AKI progression.IL-33 activates immunity done nan ‌ST2/MyD88 pathway‌, while besides exhibiting renoprotective effects via promotion of ‌ILC2s, M2 macrophages, Tregs, and Th2 responses‌. Its nett effect depends connected dosage, duration, and molecular conformation.Additionally, ‌IL-9 and IL-11‌ show context-dependent dual modulation successful AKI (Figure 4).

‌During nan pathological modulation from AKI to CKD, nan domiciled of ILs shifts from acute wounded consequence towards chronic fibrotic remodeling.‌ IL-1β tin induce renal tubular epithelial compartment senescence and pro-fibrotic facet merchandise successful hypoxic microenvironments.

IL-18 exacerbates fibrosis by promoting inflammatory infiltration and M2 macrophage transformation. Conversely, IL-10 tin suppress inflammation and M1 polarization, while IL-22 antagonizes TGF-β1-induced fibrosis by activating Jagged1/Notch1 signaling. The pro-fibrotic effects of ILs play a important driving domiciled successful AKI-CKD progression.

Therapeutic imaginable of ILs successful AKI‌

Targeted therapies based connected ILs signaling pathways person emerged arsenic caller strategies for AKI intervention. The IL-1 family fusion macromolecule Rilonacept (neutralizing IL-1α/β) and IL-17A/C neutralizing antibodies tin efficaciously alleviate inflammatory responses. IL-18 inhibitors simultaneously trim renal tubular apoptosis and hold fibrosis, while IL-22 modulation specifically alleviates cisplatin-induced nephrotoxicity.

Additionally, IL-33 monoclonal antibodies tin forestall cardiac wounded pursuing AKI. Compared to interventions targeting ILs, therapies targeting ILs receptors whitethorn connection greater advantages by blocking aggregate pathogenic ligands (e.g., IL-1α/β) and comprehensively terminating downstream signaling pathways.

Furthermore, engineered extracellular vesicle (EV) exertion has opened caller avenues: IL-10-containing EVs heighten IL-10 targeting and trim nan consequence of AKI-to-CKD progression, while IL-37-encapsulated neutrophil membrane vesicles (N-MVs) importantly amended renal ischemia-reperfusion wounded by promoting angiogenesis and exerting anti-inflammatory effects. These advances item nan sizeable therapeutic imaginable of targeting ILs for AKI treatment.

Future perspectives

The authors comprehensively elaborate connected nan diverseness and complexity of ILs' roles successful AKI pathogenesis. The reappraisal besides describes really ILs coordinate immune compartment activation and mediate crosstalk betwixt these cells and renal parenchymal cells, establishing a equilibrium betwixt pro-inflammatory/anti-inflammatory responses and injury/repair processes.

ILs-based targeted therapeutic strategies (e.g., specifically targeting peculiar ILs aliases their receptors) and emerging EV technologies show important imaginable for AKI treatment.

Source:

Journal reference:

Ji, Y., et al. (2025). Mechanisms Underlying nan Impact of Interleukin Family connected Acute Kidney Injury: Pathogenesis, Progression, and Therapy. Research. doi.org/10.34133/research.0738