Podocyte Death in Diabetic Kidney Disease: Potential Molecular Mechanisms and Therapeutic Targets

Abstract

Cell deaths maintain the normal function of tissues and organs. In pathological conditions, the abnormal activation or disruption of cell death often leads to pathophysiological effects. Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is linked to high mortality and morbidity rates, imposing a substantial burden on global healthcare systems and economies. Loss and detachment of podocytes are key pathological changes in the progression of DKD. This review explores the potential mechanisms of apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and podoptosis in podocytes, focusing on how different cell death modes contribute to the progression of DKD. It recognizes the limitations of current research and presents the latest basic and clinical research studies targeting podocyte death pathways in DKD. Lastly, it focuses on the future of targeting podocyte cell death to treat DKD, with the intention of inspiring further research and the development of therapeutic strategies.

Keywords: apoptosis; autophagy; cell death; diabetic kidney disease; ferroptosis; necroptosis; podocyte; pyroptosis.

Figure 1

Podocytes undergo distinct cell death in a high-glucose (HG) environment, which disrupts their cellular structure. Within the kidney, the glomerular filtration barrier (GFB) is composed of three distinctive cellular layers, arranged in an inner-to-outward sequence: fenestrated endothelial cells, the GBM, and podocyte foot processes. The abundant fenestrated endothelial cells serve as the first barrier of GFB. The second barrier is formed by the GBM, which is jointly synthesized and secreted by endothelial cells and podocytes. The third barrier is established through the adherent junction of podocyte foot processes, called slit diaphragms (SDs), ensuring selective blood filtration. Damaged podocytes, showing foot process effacement, experience detachment from the basement membrane, resulting in developed proteinuria. Created with BioRender.com.

Figure 2

Under HG conditions, the activation of mTOR inhibits autophagy by suppressing the ULK1 complex. Conversely, AMPK negatively modulates mTOR activity, thereby promoting the induction of autophagy. The PI3K III complex is essential for the induction of autophagy. The Atg genes regulate autophagosome formation through the Atg12–Atg5 and LC3-II complex. Atg12, involving Atg7 and Atg10, binds to Atg5 in a ubiquitin-like reaction, forming a large complex that promotes autophagosome synthesis. Pro-LC3 is converted to cytosolic LC3-I by the action of the Atg4 protease. LC3-I, with the participation of Atg7 and Atg3, attaches to phosphatidylethanolamine (PE) to form lipidated LC3, or LC3-II, which adheres to the autophagosomal membrane, regulating various steps in autophagosome formation. mTOR: mechanistic target of rapamycin; PI3K: phosphoinositide 3-kinase; AMPK: AMP activated protein kinase; Atg: autophagy-related genes; RAS (renin–angiotensin system); Rheb (Ras homolog protein enriched in brain); TSC1 (Tuberous Sclerosis Complex 1) or TSC2; ULK1 (UNC-51-like kinase 1); VPS (vascular permeability factor); FIP200 (focal adhesion kinase family interacting protein of 200 kDa); PE(phosphatidylethanolamine); LC3 (microtubule-associated protein 1 light chain 3); PAS (pre-autophagosomal structure). Created with BioRender.com.

Figure 3

Pyroptosis primarily occurs through three main pathways: inflammasomes induce the cleavage of gasdermin D (GSDMD) or inflammatory precursors (such as pro-IL-1β and pro-IL-18), via caspase-1 activation, resulting in the formation of membrane pores and subsequent pyroptotic activation. Caspase-4/5/11 directly senses bacterial lipopolysaccharides (LPS) and cleaves GSDMD, leading to the generation of its N-terminal fragment, which promotes cell membrane pore formation, causing membrane rupture and subsequent activation of pyroptosis via non-inflammatory body pathway. TNF-α-activated caspase-8 facilitates the cleavage of GSDMD, generating GSDMD-N, which ultimately drives the process of pyroptosis. Created with BioRender.com.

Figure 4

A schematic illustration of apoptosis mechanism. The activation of the intrinsic apoptotic pathway occurs when mitochondrial function is disrupted in response to various stress-inducing factors, including DNA damage, endoplasmic reticulum (ER) stress, and reactive oxygen species [118]. The key regulators of the intrinsic apoptosis pathway are the B-cell lymphoma-2 (Bcl-2) family proteins, which consist of pro-apoptotic Bcl-2 homology-3 (BH3)-only proteins (Bcl-2 interacting mediator of cell death (BIM), BH3-interacting domain death agonist (BID), p53-upregulated modulator of apoptosis (PUMA), Bcl-2-modifying factor (BMF), phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, also known as NOXA), BCL-2-interacting killer (BIK), BCL-2-associated agonist of cell death (BAD)), activator of apoptosis harakiri (HRK), prosurvival proteins (BCL-2, BCL-2-like 1 (BCL-XL), BCL-2-like 2 (BCL-W), myeloid cell leukemia-1 (MCL-1), BCL-2-related protein A1 (A1/BFL-1), and apoptosis effectors (BCL-2-associated X protein (BAX), BCL-2 antagonist/killer 1 (BAK), and BCL-2-related ovarian killer (BOK)) [119,120]. Under normal physiological conditions, the pro-survival BCL-2 proteins can bind and inhibit the effectors of apoptosis to prevent PCD [121]. BH3-only proteins exhibit a high binding affinity to the prosurvival proteins [122]. Upon activation, BAX and BAK form oligomers, leading to a change in the mitochondrial membrane potential (MOMP), subsequently releasing cytochrome C and the second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding proteins with low pI (Smac/DIABLO) [123,124]. The released factors facilitate apoptosis by activating the caspase cascade [125], ultimately resulting in the proteolytic cleavage of numerous proteins, culminating in cell death [126,127]. The activation of the extrinsic pathway is initiated by death receptors within the TNF receptor superfamily, such as focal adhesion complexes (FAS) receptor (CD95/APO-1), tumor necrosis factor receptor (TNFR1) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors (DR4/DR5) [128]. Upon binding of ligands to these membrane receptors, downstream signaling cascades are initiated. The process begins with receptor clustering, followed by recruitment of adapter proteins such as Fas-associating protein with a novel death domain (FADD) and TNFR1-associated signal transducer (TRADD), which form the death-inducing signaling complex (DISC) [129,130]. The formation of DISC activates caspase-8 (a member of the cysteine protease family), subsequently triggering a proteolytic cascade that leads to the degradation of critical proteins and ultimately cell demise [99,131]. Created with BioRender.com.

Figure 5

Necroptosis, a caspase-independent form of PCD, involves a process that requires mixed lineage kinase domain-like (MLKL) to undergo receptor-interacting protein kinase 3 (RIPK3)-dependent phosphorylation. This event facilitates the formation of pore complexes on the cellular membrane, ultimately resulting in cellular swelling and membrane rupture. Created with BioRender.com.

Figure 6

Excessive intracellular iron ions or impaired normal metabolism can lead to their accumulation. Within cells, iron ions may undergo oxidation by ROS to form trivalent iron (Fe³⁺), generating highly reactive free radicals, such as hydrogen peroxide (H₂O₂) and hydroxyl radicals (•OH). These free radicals can initiate oxidative reactions with biomolecules such as lipids, proteins, and nucleic acids, resulting in damage to cell membranes, organelles, and essential cellular molecules, This ultimately leads to cellular dysfunction and cell death. Created with BioRender.com.