Qisheng Lin

Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regulated cell death, is driven by iron-dependent lipid peroxidation and has been implicated in AKI pathogenesis. Emerging evidence suggests that lipophagy - a selective autophagic degradation of lipid droplets - potentiates ferroptosis, though the upstream regulatory mechanisms remain poorly understood. ESRRA (estrogen related receptor, alpha), a key transcriptional regulator of fatty acid metabolism and macroautophagy/autophagy, may play a critical role in this process. In this study, we identified ESRRA as a pivotal transcription factor in proximal tubular epithelial cells using single-cell transcriptomic analysis. To investigate its functional role, we employed wild-type mice and tubular epithelial cell-specific Esrra deficient mice to establish AKI models. Our findings demonstrated that ESRRA exerted a protective effect by modulating the RAB7-dependent lipophagy-ferroptosis axis. Furthermore, integrating chromatin Immunoprecipitation (ChIP)-seq and JASPAR database analyses, we predicted PIK3CA as a direct transcriptional target of ESRRA. Mechanistically, ESRRA bind to a specific promoter region within Pik3ca, enhancing its expression and subsequently activating the AKT-MTOR signaling pathway, which is required for the suppression of RAB7 mediated lipophagy in renal tubular epithelial cells, thereby attenuating AKI progression.

Thyroid storm is a life‐threatening endocrine emergency with a mortality rate of up to 17%. Standard treatment includes antithyroid drugs (ATD), β‐blockers, and glucocorticoids. However, some patients may require blood purification therapies, such as plasmapheresis, due to the ineffectiveness of standard treatments or contraindications like agranulocytosis. We report the case of a 38‐year‐old female with Graves' disease who was admitted for thyroid storm (Burch–Wartofsky score of 70) combined with encephalopathy, presenting with impaired consciousness, seizures, and leukopenia (1.82 × 10 ⁹ /L). Due to contraindications for ATD, she was treated with double filtration plasmapheresis (DFPP). After three sessions, her anti‐thyrotropin receptor antibodies (TRAb > 40–29.8 IU/L) and thyroid hormones (FT4 88.7–19.7 pmol/L) significantly decreased, and her consciousness improved. She was later transitioned successfully to oral ATD upon discharge. Plasmapheresis can rapidly remove thyroid hormones and autoantibodies, particularly useful in cases where ATD is ineffective or contraindicated. While international reports predominantly describe plasma exchange (PE), this case is the first to suggest the efficacy and safety of DFPP in treating thyroid storm with thyrotoxic encephalopathy. DFPP selectively removes large‐molecule antibodies while minimizing the use of blood products and albumin loss. For severe thyroid storm patients, early plasmapheresis may improve prognosis; however, the optimal timing, modality, and dosing require further investigation.

Common intronic enhancer SNPs in Shroom3 associate with CKD in GWAS, although there is paucity of detailed mechanism. Previously, we reported a role for Shroom3 in mediating crosstalk between TGFβ1- & Wnt/Ctnnb1 pathways promoting renal fibrosis (TIF). However, beneficial roles for Shroom3 in proteinuria have also been reported suggesting pleiotropic effects. Here we focused on identifying the specific profibrotic Shroom3 motif. Given known therapeutic roles for Rho-kinase inhibitors in experimental CKD, and the established interaction between Shroom3 and Rock via its ASD2 domain, we hypothesized that Shroom3-mediated ROCK activation played a crucial role in its profibrotic function in high expressors. To test this hypothesis, we developed transgenic mice and cell lines that inducibly overexpressed wild-type- (WT-Sh3) or ASD2-domain deletion- Shroom3 (ASD2Δ-Sh3). Prior scRNAseq data showed that during TIF, Shroom3 and Rock co-expression occurred in injured tubular cells and fibroblasts, highlighting cell-types where this mechanism could be involved. Using HEK293T cells, we first confirmed absent ROCK binding and inhibited TGFβ1-signaling with ASD2Δ-Sh3-overexpression vs WT-Sh3. In mIMCD cells, ASD2Δ-Sh3 overexpression, reduced Rock activation (phospho-MYPT1), pro-fibrotic and pro-inflammatory transcripts vs WT-Sh3. Fibroblast proliferation (3T3) was also reduced with ASD2Δ-Sh3. In vivo , we studied ureteric obstruction (UUO) and Aristolochic nephropathy (AAN) as TIF models. In AAN, inducible global-, or Pan-tubular specific-, WTSh3-overexpression showed increased azotemia, and TIF vs ASD2Δ-Sh3 mice. WT-Sh3 mice consistently showed significant enrichment of Rho-GTPase, TGFβ1- and Wnt/CtnnB1- signaling in kidney transcriptome, paralleling Shroom3-coexpressed genes in tubulo-interstitial transcriptomes from human CKD. In UUO, again WT-Sh3 mice recapitulated increased fibrosis vs ASD2Δ-Sh3. Importantly, ASD2Δ-Sh3 did not develop albuminuria vs WT-Sh3, while mutating a disparate Fyn-binding Shroom3 motif induced albuminuria in mice, suggesting motif-specific roles for Shroom3 in the kidney. Hence, our data show a critical role for the Rock-binding, ASD2-domain in mediating TIF in milieu of Shroom3 excess, with relevance to human CKD.

Background: Patients undergoing peritoneal dialysis (PD) often face nutritional deficiencies due to inadequate intake, nutrient loss, insufficient dialysis, and a state of micro-inflammatory. Traditional nutritional management methods have not fully met personalized needs. Therefore, this study aimed to develop and evaluate an application for generating recipes based on Generative Pre-trained Transformers to improve the nutritional status of these patients.Methods: This self-controlled prospective study included 35 patients undergoing PD from January to February 2024. The study was divided into two phases: the initial phase involved conventional dietary education under PD management, followed by a second phase where a new GPT-based dietary guidance tool was introduced. Patients adhered to the diets recommended by the tool. Nutritional intervention effects were assessed by comparing serum prealbumin, albumin, and phosphate levels before and after the intervention.Results: After the intervention, the mean prealbumin levels significantly improved from 289.04 ± 74.60 mg/L to 326.72 ± 78.89 mg/L (p = 0.001). Although there was no statistical significance, the serum albumin levels in patients increased from 34.70 ± 5.94 g/L to 35.66 ± 5.14 g/L (p = 0.153). Serum phosphate levels remained stable and within safe limits (p = 0.241).Conclusion: The AI-based recipe generation application significantly improved serum prealbumin levels in PD patients without causing adverse changes in phosphate levels, confirming its efficacy and safety in nutritional management for these patients. This study highlights the potential and practical value of AI technology in nutritional management for patients with chronic disease, providing important evidence for future clinical applications.

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI—induced by contrast media, ischemia–reperfusion injury, cisplatin, and folic acid—to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1–UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

Morphometric estimates of mean or individual glomerular volume (MGV, IGV) have biological implications, over and above qualitative histologic data. However, morphometry is time‐consuming and requires expertise limiting its utility in clinical cases. We evaluated MGV and IGV using plastic‐ and paraffin‐embedded tissue from 10 control and 10 focal segmental glomerulosclerosis (FSGS) mice (aging and 5/6th nephrectomy models) using the gold standard Cavalieri (Cav) method versus the 2‐profile and Weibel–Gomez (WG) methods and a novel 3‐profile method. We compared accuracy, bias and precision, and quantified results obtained when sampling differing numbers of glomeruli. In both FSGS and controls, we identified an acceptable precision for MGV of 10‐glomerular sampling versus 20‐glomerular sampling using the Cav method, while 5‐glomerular sampling was less precise. In plastic tissue, 2‐ or 3‐profile MGVs showed greater concordance with MGV when using Cav, versus MGV with WG. IGV comparisons using the same glomeruli reported a consistent underestimation bias with both 2‐ or 3‐profile methods versus the Cav method. FSGS glomeruli showed wider variations in bias estimation than controls. Our 3‐profile method offered incremental benefit to the 2‐profile method in both IGV and MGV estimation (improved correlation coefficient, Lin's concordance and reduced bias). In our control animals, we quantified a shrinkage artifact of 52% from tissue processed for paraffin‐embedded versus plastic‐embedded tissue. FSGS glomeruli showed overall reduced shrinkage albeit with variable artifact signifying periglomerular/glomerular fibrosis. A novel 3‐profile method offers slightly improved concordance with reduced bias versus 2‐profile. Our findings have implications for future studies using glomerular morphometry.

Chronic kidney disease affects approximately 14.3% of people worldwide. Tubulointerstitial fibrosis is the final stage of almost all progressive CKD. To date, the pathogenesis of renal fibrosis remains unclear, and there is a lack of effective treatments, leading to renal replacement therapy. Mitophagy is a type of selective autophagy that has been recognized as an important way to remove dysfunctional mitochondria and abrogate the excessive accumulation of mitochondrial-derived reactive oxygen species (ROS) to balance the function of cells. However, the role of mitophagy and its regulation in renal fibrosis need further examination. In this study, we showed that mitophagy was induced in renal tubular epithelial cells in renal fibrosis. After silencing BNIP3, mitophagy was abolished in vivo and in vitro, indicating the important effect of the BNIP3-dependent pathway on mitophagy. Furthermore, in unilateral ureteral obstruction (UUO) models and hypoxic conditions, the production of mitochondrial ROS, mitochondrial damage, activation of the NLRP3 inflammasome, and the levels of αSMA and TGFβ1 increased significantly following BNIP3 gene deletion or silencing. Following silencing BNIP3 and pretreatment with mitoTEMPO or MCC950, the protein levels of αSMA and TGFβ1 decreased significantly in HK-2 cells under hypoxic conditions. These findings demonstrated that HIF1α-BNIP3-mediated mitophagy played a protective role against hypoxia-induced renal epithelial cell injury and renal fibrosis by reducing mitochondrial ROS and inhibiting activation of the NLRP3 inflammasome.

Ferroptosis is a new type of cell death caused by the lack of glutathione peroxidase 4 (GPX4) and the imbalance of cellular redox. It is characterized by the accumulation of lipid peroxides on cell membranes. Multiple regulatory pathways of ferroptosis include the GPX4, glutamate-cystine antiporter (System Xc^–), lipid metabolism, and iron metabolism pathways. Recent studies have reported that autophagy-dependent ferroptosis (ferroptosis meditated by ferritinophagy, lipophagy, and clockophagy) plays a significant role in the occurrence of several diseases, including diseases affecting the nerves, liver, lungs, and kidneys. This review provides an overview of research progress made on autophagy-dependent ferroptosis in kidney diseases.