Related Experiment Video

Updated: Jun 23, 2026

Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells
06:23

Modeling Hypoxia/Reoxygenation Injury in Proximal Tubular Epithelial Cells

Published on: November 21, 2025

Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis

Heitham T Hassoun1, Mihaela L Lie, Dmitry N Grigoryev

  • 1Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. hhassou1@jhmi.edu

American Journal of Physiology. Renal Physiology
|May 1, 2009
PubMed

Insights

Acute kidney injury (AKI) triggers lung apoptosis, particularly in endothelial cells, contributing to distant organ damage. Inhibiting caspases or TNFR signaling mitigates this lung injury, revealing a key mechanism in AKI complications.

Area of Science:

  • Molecular Biology
  • Pathophysiology
  • Renal Medicine

Background:

  • Acute kidney injury (AKI) is a significant cause of mortality, with distant organ effects poorly understood.
  • Existing data suggest inflammation and apoptosis play roles in AKI-induced lung dysfunction.
  • Pulmonary apoptosis is a known mechanism contributing to acute lung injury (ALI).

Purpose of the Study:

  • To investigate the hypothesis that AKI induces pulmonary proapoptotic pathways, exacerbating lung injury and inflammation.
  • To identify specific molecular mechanisms linking kidney injury to lung dysfunction.
  • To explore therapeutic targets for mitigating AKI-related lung injury.

Main Methods:

  • A mouse model of ischemic AKI was used with a candidate gene discovery approach focusing on lung apoptosis.
  • Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), active caspase-3 (aC3) assays, immunoblotting, and immunohistochemistry (IHC) were employed.
  • Caspase inhibition (Z-VAD-FMK) and genetic deletion of TNFR (TNFR(-/-) mice) were used to assess mechanistic roles.

Main Results:

  • AKI induced significant upregulation of 66 apoptosis-related genes in the lungs, including TNFR superfamily members.
  • Kidney ischemia-reperfusion injury (IRI) led to pulmonary apoptosis, predominantly in endothelial cells (identified by CD34 colocalization).
  • Caspase inhibition reduced lung microvascular changes, and TNFR(-/-) mice lacked AKI-induced pulmonary apoptosis.

Conclusions:

  • Pulmonary endothelial apoptosis is a direct mediator of distant organ dysfunction in experimental AKI.
  • The tumor necrosis factor receptor (TNFR) pathway is implicated in AKI-induced pulmonary apoptosis.
  • Targeting apoptotic pathways, such as caspase inhibition, shows therapeutic potential for AKI-related lung injury.

More Related Videos

Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice09:09

Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice

Published on: August 9, 2013

Related Concept Videos

Acute Kidney Injury I: Introduction01:22

Acute Kidney Injury I: Introduction

Introduction:Acute Kidney Injury (AKI) describes a swift decrease in kidney function occurring over hours to days, characterized by the kidneys' failure to remove waste products from the bloodstream. This leads to dangerous complications like metabolic acidosis, fluid overload, and electrolyte imbalances, such as hyperkalemia, which can cause life-threatening arrhythmias. AKI is common in both hospital and outpatient settings, often triggered by dehydration, sepsis, or exposure to nephrotoxic...
Acute Kidney Injury II: Pathophysiology01:29

Acute Kidney Injury II: Pathophysiology

Acute kidney injury (AKI) causes are categorized into three primary categories based on the location of the injury: prerenal, intrarenal (or intrinsic), and postrenal causes. This classification guides clinical management and illustrates how different pathways can impair kidney function.Etiology and Pathophysiology of Acute Kidney Injury1. Prerenal causesEtiology: Prerenal Acute Kidney Injury, the most common type, occurs when reduced blood flow to the kidneys decreases filtration capacity...
Cellular Injury IV: Necrosis01:16

Cellular Injury IV: Necrosis

Necrosis is a form of irreversible cell death caused by severe injury such as ischemia, toxins, or trauma. Unlike programmed cell death, it is an uncontrolled, pathological process that typically provokes inflammation in surrounding tissues.Pathophysiologic ChangesNecrosis begins when cells sustain critical damage, leading to swelling of organelles, particularly mitochondria, and rapid ATP depletion. As energy levels decline, membrane ion pumps fail, leading to calcium influx and eventually,...
Cellular Injury I: Introduction01:00

Cellular Injury I: Introduction

Cellular injury occurs when a cell cannot maintain homeostasis or adapt to stressors such as hypoxia, toxins, or trauma. Depending on severity and duration, injury may be reversible, allowing recovery, or irreversible, leading to cell death.General Mechanisms of Cell InjuryAlthough causes vary, most cellular injuries arise from a few key mechanisms that disrupt essential functions and often amplify one another. Cell survival depends on the extent and balance of these disturbances.ATP depletion...
Acute Kidney Injury III: Clinical Manifestations01:29

Acute Kidney Injury III: Clinical Manifestations

Acute Kidney Injury (AKI) progresses through distinct clinical phases: the oliguric, diuretic, and recovery phases, each marked by unique manifestations and challenges.Oliguric Phase:The oliguric phase is the initial stage of AKI, typically lasting 10 to 14 days. This phase is marked by a significant reduction in urine output, usually less than 400 mL per day, indicating decreased kidney function. Fluid retention is a prominent feature, leading to symptoms such as edema, hypertension, and...
Acute Kidney Injury IV: Diagnostic Studies and Prevention01:30

Acute Kidney Injury IV: Diagnostic Studies and Prevention

Accurate diagnosis and effective prevention are critical in managing Acute Kidney Injury (AKI), which is linked to high mortality rates ranging from 10% to 80%. Timely recognition of at-risk patients and careful monitoring can significantly reduce the likelihood of kidney damage.Diagnostic Assessments:The diagnostic process starts with a comprehensive medical history to identify prerenal, intrarenal, and postrenal causes.Prerenal causes, such as dehydration, hypotension, or blood loss, should...