Kerim Mutig

Interleukin-15 (IL-15) is an immunoregulatory cytokine also recognized as a myokine, with experimentally demonstrated cytoprotective and metabolic effects. Renal tubular epithelial cells (TECs) and podocytes express components of the IL-15 receptor system, but the role of IL-15 in exercise-associated renal adaptation remains unclear. This review distinguishes evidence from renal experimental models from hypotheses regarding exercise-induced renoprotection. Cell-culture and preclinical studies support a role for IL-15 in promoting TEC survival and attenuating profibrotic responses. Separate studies in podocytes demonstrate a functional role for STAT5 in autophagy regulation and improvements in mitochondrial fusion and respiration in response to IL-15, with optic atrophy 1 (OPA1) implicated in the latter response. These findings do not establish a single integrated pathway or demonstrate that the same protective mechanisms operate during exercise. Strenuous exercise may transiently increase tubular stress- or injury-associated biomarkers; however, these increases do not necessarily indicate clinically significant acute kidney injury (AKI) and should be interpreted alongside measures of renal function and the clinical context. We outline a conceptual framework that distinguishes potentially protective responses in renal parenchymal cells from IL-15-dependent immune activation that may contribute to injury in selected disease settings. Cytokine availability, exposure duration, mode of presentation, receptor composition, and inflammatory context may influence these outcomes, but their roles in renal responses to exercise remain to be established. An increase in circulating IL-15 alone does not establish its skeletal muscle origin, delivery to the kidney, or biological activity in renal target cells. The key unresolved question is whether IL-15 produced by skeletal muscle in response to exercise reaches renal target cells in a biologically active form and confers measurable renoprotection.

Uromodulin (Umod) is the most abundant urinary protein produced by the thick ascending limb (TAL) and distal convoluted tubule (DCT) of the kidney. Its physiological functions range from the protection against urinary tract infections (UTIs) and prevention of urinary stones to the modulation of ion transport along the distal nephron. Apart from the apical release into urine, Umod is delivered to the renal interstitium and serum via basolateral secretion to fulfil immunoregulatory tasks. Mutations and polymorphisms in the Umod gene have been associated with kidney and cardiovascular diseases, whereas serum and urinary Umod levels are emerging as biomarkers of renal and cardiovascular risks and conditions. Aging is associated with a gradual decline in both serum and urinary Umod levels, which may contribute to increased risk of UTI and kidney stones and decreased urinary concentration ability in older adults. The present review synthesizes the available information on endocrine regulation of Umod production and release during healthy and pathophysiological aging to specify translational perspectives of targeting the Umod biology and assist by interpretation of serum and urinary Umod levels as biomarkers of renal and cardiovascular health.

Acute kidney injury (AKI) is a life-threatening event prevalent in hospitalized patients but also not rare among endurance sports athletes. Hypoxia, oxidative stress, and sterile inflammation are the key pathophysiological factors driving kidney damage in AKI. Zinc is an essential trace element required for the intact function of approximately 3000 proteins (~10% of the human proteome), including over 300 enzymes for which zinc serves as a cofactor. Cell biological tasks of zinc signaling include adaptive responses to hypoxia and oxidative stress, as well as anti-inflammatory effects. The underlying molecular pathways involve modulation of hypoxia-inducible factor signaling, suppression of reactive oxygen species (ROS) generation, and inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), the latter being the major pro-inflammatory transcription factor. As a catalytic cofactor for the “classical” histone deacetylases, zinc is essential for epigenetic control of gene expression, thereby exerting further adaptive effects. Apart from the intracellular zinc signaling, extracellular zinc elicits cytoprotective and anti-inflammatory effects via the G Protein-Coupled Receptor 39 (GPR39). GPR39 activation by zinc binding may exert antioxidant and anti-inflammatory effects mediated by the zinc-finger protein A20 (TNFAIP3) and NF-κB suppression, followed by reduced production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), and IL-6. At the same time, GPR39 signaling may stimulates the release of the anti-inflammatory cytokine IL-10, thus shifting the kidney tissue towards an anti-inflammatory milieu, promoting renal recovery. The present review focuses on the role of zinc in AKI to identify potential therapeutic strategies targeting zinc signaling for renoprotection and biomarker-based risk stratification.

Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin receptor kinase B (TrkB) are classically associated with neuroplasticity, but increasing evidence suggests a broader role for BDNF/TrkB signaling in systemic stress adaptation beyond the central nervous system. Strenuous exercise is a model of functional stress that may become a clinically relevant renal challenge under conditions such as dehydration, heat stress, vascular vulnerability, and repeated exposure. Neuroendocrine stress activation, hemodynamic perturbations, and cytoskeletal instability are key factors that may contribute to glomerular barrier dysfunction in this setting. BDNF biogenesis is complex, and circulating BDNF largely reflects platelet-associated pools and context-dependent release. At the tissue level, BDNF/TrkB signaling can activate actin-regulatory pathways involved in cellular resilience. The podocyte is of particular interest because its actin-dependent architecture functionally parallels that of neurons and is essential for maintenance of the glomerular filtration barrier. Within this framework, BDNF/TrkB signaling may stabilize podocyte actin dynamics, reduce foot process effacement, and attenuate proteinuria. The present review focuses on the brain–kidney axis and the potential renoprotective role of BDNF/TrkB signaling, while highlighting major knowledge gaps regarding BDNF availability to glomerular cells, isoform-specific TrkB actions, and causal inference in humans exposed to repeated exercise-related renal stress. However, current human evidence is insufficient to define the dominant source and delivery route of BDNF to glomerular cells during exercise-related renal stress. Therefore, BDNF/TrkB is discussed here as a candidate modulatory/resilience pathway rather than an established causal driver.

Kidney aging is receiving growing attention in middle- to high-income societies due to increasing longevity in general population. Chronic Kidney Disease (CKD) has been widely accepted as a major non-communicable human disease affecting over 10% of the adult population in industrialized countries. CKD is mainly caused by metabolic and cardiovascular disorders such as diabetes mellitus and hypertension, disproportionally affecting older people, whereas natural kidney aging is driven by age-dependent systemic and renal low-grade inflammation. Interleukin-6 (IL-6) is the key cytokine mediating age-related inflammation. At the same time, IL-6 has been implicated in the pathophysiology of cardiovascular and renal disorders as a major pro-inflammatory cytokine. Thereby, IL-6 is placed at the intersection between natural and pathophysiological kidney aging, and the latter accelerates systemic aging and substantially limits life quality and expectancy. Growing clinical availability of IL-6 inhibitors for treatment of autoimmune and autoinflammatory disorders demands clarification of potential renal consequences as well. Available data suggests that IL-6 inhibition may be renoprotective in some kidney disorders, but the setting of kidney aging has received only minor attention. The present review focuses on the known effects of IL-6 associated with natural or pathophysiological renal aging.

[This corrects the article DOI: 10.3389/fendo.2025.1689787.].

Low-grade inflammation, both hypothalamic and systemic, sensitizes the neuroendocrine response to osmotic stimuli whose proximate cause is chronic underhydration common in older adults due to diminished thirst perception. These events drive persistent vasopressin (VP) release. VP exerts antidiuretic effects via renal V2 receptors and functions as a stress hormone through widely expressed V1a and V1b receptors. These latter actions are central to inappropriate activation of the hypothalamic-pituitary-adrenal axis observed in aging, as VP stimulates secretion of the adrenocorticotropic hormone. The resulting sustained elevations in circulating VP and cortisol contribute to metabolic, renal, and cardiovascular disorders that compromise health and lifespan in older individuals. This review reconciles the concept of microinflammation with recent molecular insights into hypothalamic osmosensitivity, proposing a model for the maladaptive hypersecretion of vasopressin in advanced age. This framework may inform the development of targeted interventions to normalize VP secretion, thereby mitigating the metabolic, cardiovascular, and renal diseases that disproportionately affect older adults.

Sterile inflammation with ensuing immune-mediated kidney damage has been implicated in pathophysiology of acute and chronic kidney diseases. Disinhibition of interleukin 1 (IL-1) signaling triggers local inflammation of renal tissue and may initiate or aggravate systemic inflammatory response. The IL-1α isoform is released by many cell types during cell necrosis to attract immune cells, whereas the IL-1β isoform is secreted by immune cells to amplify local inflammatory responses. The unfolding of IL-1 signaling is restricted by an endogenous IL-1 receptor antagonist and a decoy IL-1 receptor variant. Pharmacological IL-1 inhibitors mimicking the natural IL-1 suppressors are instrumental in management of a broad spectrum of (auto)inflammatory disorders. Progression of several kidney diseases toward renal fibrosis has been associated with a disbalance between the pro-inflammatory and anti-inflammatory IL-1 signaling components. While IL-1 inhibitors have proven success in prevention and treatment of renal complications accompanying the autoimmune disorders, broader opportunities in kidney diseases have been expected. The present review work analyzes potential niches for IL-1 signaling in the field of nephrology.

Sterile inflammation has been increasingly recognized as a hallmark of non-infectious kidney diseases. Induction of pro-inflammatory cytokines in injured kidney tissue promotes infiltration of immune cells serving to clear cell debris and facilitate tissue repair. However, excessive or prolonged inflammatory response has been associated with immune-mediated tissue damage, nephron loss, and development of renal fibrosis. Interleukin 6 (IL-6) is a cytokine with pleiotropic effects including a major role in inflammation. IL-6 signals either via membrane-bound (classic signaling) or soluble receptor forms (trans-signaling) thus affecting distinct cell types and eliciting various metabolic, cytoprotective, or pro-inflammatory reactions. Antibodies neutralizing IL-6 or its receptor have been developed for therapy of autoimmune and chronic non-renal inflammatory diseases. Small molecule inhibitors of Janus kinases acting downstream of the IL-6 receptor, as well as recombinant soluble glycoprotein 130 variants suppressing the IL-6 trans-signaling add to the available therapeutic options. Animal data and accumulating clinical experience strongly suggest that suppression of IL-6 signaling pathways bears therapeutic potential in acute and chronic kidney diseases. The present work analyses the renoprotective potential of clinically relevant IL-6 signaling inhibitors in acute kidney injury, chronic kidney disease, and kidney transplantation with focus on current achievements and future prospects.

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation ( CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, impairs complex glycosylation, but that surface expression remains intact. Moreover, Asn-364 was necessary for channel function and complex glycosylation. Morphologic evaluation of human kidney biopsies revealed typical basolateral localization of mutant Gly167Cys ClC-Kb in cortical distal tubular epithelia. However, we detected attenuated expression of distal sodium transport proteins, changes in abundance of distal tubule segments, and hypokalemia-associated intracellular condensates from the index patient compared with control nephrectomy specimens. The present data establish what we believe are novel regulatory mechanisms of ClC-Kb activity and demonstrate nephron remodeling in humans, caused by mutant ClC-Kb, with implications for renal electrolyte handling, blood pressure control, and kidney disease.