Reiko Inagi

This study reveals the critical role of PDZD8 in maintaining endolysosomal homeostasis and regulating the TLR9-NF-κB inflammatory pathway in cisplatin-induced acute kidney injury (AKI). Loss of PDZD8 impaired endolysosomal function, suppressing TLR9 activation and downstream inflammation, leading to reduced tubular damage.

The endoplasmic reticulum (ER) is a key organelle involved in a wide range of intracellular biological processes, including Ca²⁺ homeostasis; lipid metabolism; proteostasis through protein synthesis, folding and processing of secretory and transmembrane proteins; and signal transduction. The ER forms extensive physical interactions with various intracellular organelles through the membrane contact sites, enabling direct exchange of ions and lipids without vesicular transport. At mitochondria-associated membranes, ER–mitochondria communication governs calcium transfer, lipid synthesis, mitochondrial dynamics, the unfolded protein response and inflammation, all of which are essential for maintaining cellular homeostasis. The ER also interacts with the Golgi apparatus, endosomes and plasma membrane to facilitate transfer of calcium and lipids. Disruption of ER–organelle communication contributes to the development and progression of various kidney diseases, including diabetic kidney disease, acute kidney injury and polycystic kidney disease. Accordingly, ER–organelle communication has emerged as a promising therapeutic target. Pharmacological agents such as SGLT2 inhibitors, AMPK activators, mTOR inhibitors and RAAS blockers have been shown to restore ER–mitochondria communication and alleviate kidney injury in experimental models. Advancing our understanding of ER–organelle crosstalk may offer new mechanistic insights and contribute to the optimization of current treatment strategies for kidney disease.

Lipotoxicity, defined as the excessive accumulation of lipids in non‐adipose tissues due to dysregulated lipid metabolism, is associated with several metabolic disorders, including insulin resistance, chronic kidney disease (CKD) and obesity. It contributes to renal injury through multiple interrelated mechanisms, including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, impaired autophagy, inflammation and oxidative stress, and ultimately causes damage to various renal cell types. Although current pharmacological therapies have demonstrated renoprotective effects, including renin‐angiotensin system inhibitors (RASi), sodium–glucose co‐transporter 2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and non‐steroidal mineralocorticoid receptor antagonists (NS‐MRAs), their precise mechanisms of action are not fully understood. Lipid‐lowering agents have also shown potential renal benefits in some studies, although their exact mechanisms are also still unclear. Emerging preclinical evidence indicates that these therapies may attenuate lipotoxicity via enhanced fatty acid oxidation (FAO), reduced cholesterol biosynthesis, decreased de novo lipogenesis, anti‐inflammatory and antioxidant effects and improved mitochondrial function. These effects may represent key mechanisms in the attenuation of CKD progression. This review focuses on the proposed mechanisms by which these agents may alleviate lipotoxicity. It examines the cellular responses to lipid dysregulation and finally emphasises the need for further research to clarify these pathways and their clinical relevance.

Increased blood hemoglobin concentration theoretically promotes oxygen delivery to the periphery. Clinically, in addition to recombinant human erythropoietin analogs, prolyl hydroxylase (PH) inhibitors to stabilize the expression of hypoxia‐inducible factor (HIF) protein were recently approved for the treatment of anemia in chronic kidney disease. However, whether the new agent helps enhance physical exercise capacity remains a matter of controversy. Treatment of C57BL/6J mice via oral gavage with roxadustat of 30 mg/kg three times per week for 5 weeks elevated the blood hemoglobin concentration, upregulated the HIF‐downstream gene expression of the muscle, and enhanced a high‐intensity exercise performance measured with a treadmill running exhaustion test, compared to those treated with vehicle, while total body weight or skeletal muscle mass was comparable. This physical effect depended on the increase in blood hemoglobin concentration, as confirmed by mice hemodiluted to control hemoglobin concentrations through phlebotomy followed by infusion of the approximate volume of phosphate‐buffered saline. In conclusion, oral administration of the HIF‐PH inhibitor to mice increased high‐intensity exercise capacity as well as elevated blood hemoglobin concentration. The finding implies the versatile effects on humans taking HIF‐PH inhibitors, as well as the risk of them being abused for blood doping.

Biomarkers for the prediction of diabetic kidney disease are still unsatisfactory. Although D‐amino acids have been shown to reflect kidney conditions, their efficacy in treating diabetic kidney disease (DKD) has not been demonstrated. This study explored the potential role of D‐amino acids as progression markers for DKD, an aspect not addressed previously. We performed comprehensive D‐amino acid measurements and collected the longitudinal estimated glomerular filtration rate (eGFR) data of 135 patients. We defined fast decliners (FDs) as patients exhibiting >10% decline from baseline eGFR per year and compared the D‐amino acid levels of FDs and non‐FDs. Then, we verified that D‐amino acids could predict FDs independent of creatinine levels. In patients with diabetic kidney disease, D‐serine, D‐alanine, and D‐proline were only detected in the blood, while 15 D‐amino acids were detected in the urine. Using supervised orthogonal partial least squares analysis, blood D‐serine and urine D‐amino acid levels were identified as features characterizing diabetic kidney disease. Baseline blood D‐serine levels and ratios did not differ between the FD and non‐FD groups; however, short‐term changes in blood D‐serine levels differed. This study emphasized the significance of D‐serine as a prognostic marker for DKD, an aspect not identified in previous research.

Organelle stress exacerbates podocyte injury, contributing to perturbed lipid metabolism. Simultaneous organelle stresses can occur in the kidney in the diseased state; therefore, a thorough analysis of organelle communication is crucial for understanding the progression of kidney diseases. Although organelles closely interact with one another at membrane contact sites, limited studies have explored their involvement in kidney homeostasis. The endoplasmic reticulum (ER) protein, PDZ domain–containing 8 (PDZD8), is implicated in multiple-organelle-tethering processes and cellular lipid homeostasis. In this study, we aimed to elucidate the role of organelle communication in podocyte injury using podocyte-specific Pdzd8 -knockout mice. Our findings demonstrated that Pdzd8 deletion exacerbated podocyte injury in an accelerated obesity–related kidney disease model. Proteomic analysis of isolated glomeruli revealed that Pdzd8 deletion exacerbated mitochondrial and endosomal dysfunction during podocyte lipotoxicity. Additionally, electron microscopy revealed the accumulation of abnormal, fatty endosomes in Pdzd8 -deficient podocytes during obesity-related kidney diseases. Lipidomic analysis indicated that glucosylceramide accumulated in Pdzd8 -deficient podocytes, owing to accelerated production and decelerated degradation. Thus, the organelle-tethering factor, PDZD8, plays a crucial role in maintaining mitochondrial and endosomal homeostasis during podocyte lipotoxicity. Collectively, our findings highlight the importance of organelle communication at the 3-way junction among the ER, mitochondria, and endosomes in preserving podocyte homeostasis.

Organelles are membrane-lined structures that compartmentalize subcellular biochemical functions. Therefore, interorganelle communication is crucial for cellular responses that require the coordination of such functions. Multiple principles govern interorganelle interactions, which arise from the complex nature of organelles: position, multilingualism, continuity, heterogeneity, proximity, and bidirectionality, among others. Given their importance, alterations in organelle communication have been linked to many diseases. Among the different types of contacts, endoplasmic reticulum mitochondria interactions are the best known; however, mounting evidence indicates that other organelles also have something to say in the pathophysiological conversation.