Acute kidney injury can damage far more than the kidneys. When renal blood flow is interrupted and then restored, the resulting ischemia–reperfusion injury can trigger a systemic inflammatory response that reaches the lungs, where it may produce edema, impaired oxygen exchange and acute lung injury. A study published in Pediatric Research identifies a molecular pathway that may connect these two organs: the inflammatory protein high mobility group box 1, or HMGB1, appears to cooperate with myosin heavy chain 9, known as MYH9, to suppress the protective activity of the nuclear receptor PPARγ. The research also points to the diabetes drug rosiglitazone as a possible way to interrupt this process.
The findings address a major clinical problem. Patients who develop acute kidney injury together with acute lung injury face a substantially higher risk of respiratory failure and death than patients with injury to either organ alone. The connection is not simply a consequence of fluid accumulation or reduced kidney function. Damaged kidneys can release inflammatory mediators, danger signals and cellular debris into the circulation, activating immune cells and the vascular lining throughout the body. In the lungs, this systemic response can weaken the alveolar–capillary barrier, allowing fluid and inflammatory cells to enter air spaces that are normally reserved for gas exchange.
Ischemia–reperfusion is a particularly powerful trigger for this kind of secondary injury. During a period of insufficient blood supply, kidney cells experience oxygen and energy deprivation. The sudden return of oxygenated blood, although essential for tissue survival, can generate reactive oxygen species and amplify mitochondrial stress. Injured cells release damage-associated molecular patterns, or DAMPs, which alert the innate immune system to tissue damage even in the absence of an infection. HMGB1 is one of the best-known DAMPs. Normally located in the cell nucleus, where it helps organize DNA, HMGB1 can move outside the cell after injury or active secretion and function as a potent inflammatory signal.
Extracellular HMGB1 can bind receptors such as toll-like receptors and the receptor for advanced glycation end products, initiating signaling cascades that activate nuclear factor kappa B and other inflammatory programs. These pathways can increase the production of cytokines, chemokines and adhesion molecules, encouraging immune cells to migrate into vulnerable tissues. In the lung, such signaling may promote endothelial and epithelial dysfunction, disturb fluid regulation and impair the surfactant-dependent mechanics required to keep alveoli open. The study by Ning, Kuai, Zhou and colleagues places MYH9 within this injury network, suggesting that HMGB1 does more than transmit an inflammatory message from the kidney.
MYH9 encodes non-muscle myosin IIA, a motor protein involved in actin-based cellular movement, shape changes, adhesion and barrier organization. Although myosin proteins are often associated with muscle contraction, non-muscle myosin IIA is active in many cell types, including endothelial and epithelial cells. It helps cells maintain mechanical integrity and respond to external signals. The reported HMGB1/MYH9 relationship therefore offers a potential explanation for how an inflammatory molecule can produce structural and functional changes in lung tissue. By influencing MYH9-associated signaling or cellular architecture, HMGB1 may help destabilize the pulmonary barrier while also altering gene regulation.
At the center of the proposed mechanism is PPARγ, a ligand-activated transcription factor that regulates lipid metabolism, inflammation and cellular differentiation. PPARγ is expressed in several lung cell populations and has been associated with maintenance of epithelial function and restraint of excessive inflammatory responses. When activated, it can oppose pro-inflammatory transcriptional programs and influence the expression of genes involved in oxidative stress, immune signaling and tissue repair. The study’s central claim is that HMGB1, acting through or in association with MYH9, suppresses PPARγ during renal ischemia–reperfusion, removing an important brake on lung inflammation.
That mechanism also provides a rationale for examining rosiglitazone. The drug belongs to the thiazolidinedione class and is a synthetic agonist of PPARγ. By binding the receptor, rosiglitazone can promote PPARγ-dependent transcription and potentially restore protective gene activity that has been reduced during systemic injury. In the context described by the researchers, treatment with rosiglitazone produced protective effects against lung injury following renal ischemia–reperfusion. The implication is not that the drug simply reduces inflammation in a nonspecific way, but that it may act downstream of the HMGB1/MYH9 pathway by reactivating a transcriptional program capable of preserving pulmonary tissue.
The work is important because it links three biological levels that are often studied separately: the release of an injury alarm signal from the kidney, the activity of a cytoskeletal and signaling protein, and the suppression of a nuclear receptor that helps regulate lung homeostasis. Such a chain could offer new biomarker opportunities. Elevated HMGB1 might indicate active systemic tissue damage, while changes involving MYH9 or PPARγ could provide information about the likelihood or severity of secondary lung injury. However, biomarkers must be validated in human patients, since concentrations measured in experimental models may not directly predict clinical outcomes.
The therapeutic implications are promising but require careful interpretation. Rosiglitazone is already known to have clinically important adverse effects, including fluid retention and cardiovascular concerns in susceptible patients. Those risks are especially relevant in people with kidney injury, who may already be vulnerable to altered fluid balance and cardiac stress. A treatment that activates PPARγ could also affect metabolism and immune responses in ways that differ between children and adults. The findings therefore support further investigation of PPARγ-centered therapies, but they do not establish rosiglitazone as a ready-to-use treatment for patients with acute kidney–lung injury.
The study ultimately reinforces the view that organ failure is often a network disease rather than an isolated local event. A kidney deprived of blood and then reperfused can initiate molecular signals that reshape the behavior of distant organs, with HMGB1/MYH9-mediated suppression of PPARγ emerging as a possible driver of pulmonary damage. If future work confirms the pathway in human tissue and clarifies which cells are most responsible, clinicians may be able to identify patients at risk before respiratory deterioration becomes severe. The findings from Ning, Kuai, Zhou and colleagues offer a mechanistic lead for that effort and suggest that restoring endogenous anti-inflammatory programs may be as important as blocking inflammatory signals themselves.
Subject of Research: The role of HMGB1/MYH9-mediated suppression of PPARγ in lung injury caused by renal ischemia–reperfusion, and the protective potential of rosiglitazone.
Article Title: HMGB1/MYH9 suppresses PPARγ to induce lung injury in renal ischemia-reperfusion: protective effects of Rosiglitazone
Article References: Ning, D., Kuai, Y., Zhou, Y. et al. HMGB1/MYH9 suppresses PPARγ to induce lung injury in renal ischemia-reperfusion: protective effects of Rosiglitazone. Pediatric Research (2026). https://doi.org/10.1038/s41390-026-05346-0
Image Credits: AI Generated
DOI: 10.1038/s41390-026-05346-0
Keywords: acute kidney injury, acute lung injury, renal ischemia–reperfusion, HMGB1, MYH9, PPARγ, rosiglitazone, inflammation, organ crosstalk, biomarkers
Tags: acute kidney and lung injury connectionHMGB1 and MYH9 pathwayinflammatory mediators in organ cross-talkmolecular mechanisms of organ injurypotential treatment strategies for multi-organ damagePPARγ protective rolepulmonary edema and impaired oxygen exchangerenal ischemia-reperfusion injuryrosiglitazone therapeutic potentialsystemic inflammation in ischemia-reperfusionsystemic inflammatory response
