Pengli Luo

Elevated FGF23 is associated with bone microarchitectural deterioration in chronic kidney dis-ease-mineral and bone disorder (CKD-MBD). While roxadustat (a HIF-PHI) is established for the treatment of renal anemia, its potential bone-protective effects in CKD-MBD remain unclear. We investigated whether roxadustat ameliorates femoral microarchitectural deterioration in CKD-MBD rats in association with FGF23 downregulation and restoration of Wnt/β-catenin signaling. A CKD-MBD rat model was established by unilateral nephrectomy and adenine gavage, and animals were randomized into sham, model, and roxadustat (50 or 100 mg/kg, three times weekly) groups for 8 weeks. Renal function, hematological indices, calcium-phosphate parame-ters, and femoral microarchitecture were evaluated, and target protein levels (FGF23, FGFR1, DKK1, β-catenin) were assessed by Western blotting and immunohistochemistry. Roxadustat improved renal function, ameliorated the reduction in erythroid parameters, and restored calcium-phosphate homeostasis. Systemically, it mitigated micro-inflammation by reducing serum CRP and hepcidin, and downregulated serum FGF23 levels as well as tissue FGF23 expression in kidney and bone. In conclusion, the bone-protective effect of roxadustat occurs synchronously with systemic micro-inflammation mitigation, FGF23 downregulation, and Wnt/β-catenin signaling restoration. These findings highlight its pleiotropic therapeutic potential in CKD-MBD management, suggesting a synergistic benefit associated with both systemic metabolic recovery and local skeletal regulation.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, despite therapeutic advances. Podocyte injury constitutes a critical pathogenic process in DKD. This study elucidated the role of the neonatal Fc receptor (FcRn) in DKD-associated podocyte injury. In DKD, glomerular FcRn expression was markedly elevated and inversely correlated with podocin levels. In diabetic mice, podocyte-specific FcRn deficiency significantly ameliorated insulin resistance and mitigated podocyte damage. Mechanistically, FcRn upregulation in diabetic podocytes exacerbated insulin resistance, suppressed AKT/mTOR signaling, and impaired autophagy, thereby promoting podocyte injury. These findings identify FcRn as a pivotal contributor to podocyte injury in DKD and suggest that FcRn targeting represents a promising therapeutic strategy. Article Highlights: Neonatal Fc receptor (FcRn) mediates podocyte injury in immune complex nephropathies, but its role in diabetic kidney disease (DKD) remains undefined. This study demonstrates marked FcRn upregulation in DKD podocytes and elucidates the functional consequences of podocyte FcRn deficiency. FcRn deficiency protects podocytes in DKD by restoring autophagy via enhanced insulin sensitivity and subsequent AKT/mTOR signaling activation. These findings identify FcRn as a novel therapeutic target for DKD, offering a strategy to mitigate the substantial residual risk of disease progression despite current therapies.

Diabetic nephropathy and diabetic atherosclerosis often develop together and share similar metabolic disturbances. Lipid abnormalities are common in diabetes, yet their roles in kidney and vascular injury are not fully understood. In diabetic kidney disease, altered lipid uptake, reduced fatty acid oxidation, and accumulation of harmful lipid species contribute to cellular stress, mitochondrial injury, inflammation, and fibrosis. In parallel, disordered lipid handling in the vasculature promotes endothelial dysfunction and atherosclerotic plaque development. However, not all lipid accumulation appears to be detrimental, and some findings suggest adaptive or context-dependent effects, leading to inconsistent results across studies. In this review, we summarize current evidence on lipid metabolism in diabetic nephropathy and atherosclerosis, compare shared and distinct features, and discuss ongoing controversies. We also briefly address the therapeutic relevance of targeting lipid pathways and highlight areas that require further investigation. Compared with prior reviews that mainly discussed fatty kidney as an emerging concept in chronic kidney disease research, this review specifically focuses on diabetic kidney disease and integrates kidney-specific lipid trafficking, kidney–vessel crosstalk, conflicting evidence, and mechanism-based therapeutic implications.

Objective: To assess the effects of human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) on mitochondrial damage and metabolic disorders induced by acute and chronic hypoxia in mouse kidneys.Method: Comprehensive analyses were conducted, including histopathology, mitochondrial morphology analysis, biochemical assessments, transcriptomics and metabolomics.Results: The results revealed that hUC‐MSCs significantly improved renal mitochondrial integrity and maintained mitochondrial dynamic balance under both acute and chronic hypoxia. This improvement was achieved by upregulating the expression of peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha, which ultimately enhanced mitochondrial function. Furthermore, hUC‐MSCs reprogrammed renal metabolic disorders, particularly improvements in urea and purine metabolic dysfunction, increased fatty acid oxidation and amelioration of lipid metabolic disorders.Conclusion: These findings suggest that hUC‐MSCs could be part of a promising strategy for enhancing renal health and metabolic stability in individuals exposed to high altitudes or other hypoxic environments, highlighting their potential therapeutic value in addressing hypoxia‐induced mitochondrial damage and renal metabolic disorders.

Purpose: Our study aims to investigate specific changes in serological 5-MTP expression in sepsis-associated acute kidney injury (SA-AKI) patients and assess its potential as a biomarker for SA-AKI occurrence. Additionally, we seek to evaluate the predictive value of 5-MTP in long-term clinical prognosis following SA-AKI. Patients and Methods: A prospective cohort study included 31 healthy controls and 78 patients diagnosed with sepsis at the Affiliated Hospital of Qinghai University. Following the collection of serological samples, 5-MTP levels were determined using targeted metabolomics.Additionally, we collected clinical data, including blood routine, biochemical, inflammatory indicators and severity of disease. Spearman correlation, COX regression analysis and Kaplan-Meier curves were used to evaluate the correlation between serum 5-MTP and renal function and the value of prognosis. Results: The findings revealed that serum 5-MTP levels were significantly elevated in SA-AKI patients compared to both the healthy control and sepsis groups(P< 0.05), and were associated with Scr, BUN, and eGFR levels(P< 0.05). Additionally, 5-MTP was identified as an independent influencing factor for all-cause mortality in patients with sepsis and SA-AKI. Higher levels of 5-MTP were linked to faster recovery of kidney function, while lower levels were associated with increased 90-day all-cause mortality in SA-AKI patients. Conclusion: 5-MTP may have a protective role in the development of SA-AKI, and an early increase in serological expression of 5-MTP could positively impact the prognosis of sepsis and SA-AKI.

Purpose: The effects of 5-methoxytryptophan (5-MTP) on mitophagy in sepsis-induced acute kidney injury (S-AKI) and its possible role in the Nrf2/HO-1 signaling pathway are unclear. In this study, we aimed to examine the levels of serum 5-MTP and mitophagy in patients with S-AKI and to evaluate the influence of 5-MTP on a lipopolysaccharide(LPS)-induced AKI model. Additionally, we sought to elucidate the mechanisms by which 5-MTP regulates mitophagy via Nrf2 mediation. Patients and Methods: We initially included 52 patients with sepsis, 25 of whom were diagnosed with AKI, and used metabolomics to analyze the serum levels of 5-MTP. We investigated the effects of exogenous 5-MTP on the kidneys of a mouse model with LPS-induced AKI. We explored the underlying mechanisms by assessing oxidative stress and mitophagy in the kidneys following the administration of different doses of 5-MTP to S-AKI mice. In addition, we used ML385 to inhibit Nrf2 expression and assessed mitophagy levels in kidney damage to investigate the specific mechanism by which 5-MTP mitigates S-AKI. Results: The plasma 5-MTP levels were significantly higher in patients with S-AKI than in those with sepsis, showing a correlation with renal function. Administration of 5-MTP led to a decrease in inflammatory and oxidative stress reactions and stimulated the Nrf2 signaling pathway to alleviate kidney injury following the induction of sepsis. However, this protective effect was reversed by ML385. In S-AKI, 5-MTP therapy enhanced mitophagy and decreased kidney injury by upregulating the Nrf2/HO-1 pathway. Conclusion: Serum 5-MTP levels correlate with renal function and upregulate Nrf2 expression by activating the Nrf2 signaling pathway, thereby promoting renal tubular mitophagy and alleviating S-AKI.

Podocytopathies encompass kidney diseases where direct or indirect podocyte injury leads to proteinuria or nephrotic syndrome. Although Semaphorin3A (Sema3A) is expressed in podocytes and tubular cells in adult mammalian kidneys and has a common effect on the progression of podocyte injury, its mechanism remains unclear. Previous studies have shown increased Sema3A expression in various glomerulopathies, indicating a gap in understanding its role. In this study, analysis of human data revealed a positive correlation between the levels of urinary Sema3A and Podocalyxin (PCX), suggesting a close relationship between Sema3A and podocyte loss. Furthermore, the impact of Adriamycin on podocytes was investigated. Adriamycin induced podocyte migration and apoptosis, along with an increase in Sema3A expression, all of which were ameliorated by the inhibition of Sema3A. Importantly, TRPC5 was found to increase the overexpression of Sema3A in podocytes. A TRPC5 inhibitor, AC1903, alleviated podocyte migration and apoptosis, inhibiting the formation of lamellar pseudopodia in the podocyte cytoskeleton by lowering the expression of Rac1. Furthermore, AC1903 relieved massive albuminuria and foot process effacement in the kidneys of Adriamycin-treated mice in vivo. In conclusion, our findings suggest that Sema3A may impact the cytoskeletal stability of podocytes through TRPC5 ion channels, mediated by Rac1, ultimately leading to foot process effacement. Notably, AC1903 demonstrates the potential to reverse Adriamycin-induced foot process fusion and urine protein. These results contribute to a deeper understanding of the mechanisms involved in podocytopathies and highlight the therapeutic potential of targeting the Sema3A-TRPC5 pathway.

Renal diseases, particularly acute kidney injury (AKI) and chronic kidney disease (CKD), are significant global health challenges. These conditions impair kidney function and can lead to serious complications, including cardiovascular diseases, which further exacerbate the public health burden. Currently, the global AKI mortality rate is alarmingly high (20%–50%); CKD is projected to emerge as a major global health burden by 2040. Existing treatments such as hemodialysis and kidney transplantation have limited effectiveness and are often associated with adverse effects. Mesenchymal stem cells (MSCs) offer considerable potential for treating renal diseases owing to their regenerative and immunomodulatory properties. Thus, this review focuses on the application of MSCs in renal disease, discusses fundamental research findings, and evaluates their application in clinical trials. Moreover, we discuss the impact and safety of MSCs as a therapeutic option and highlight challenges and potential directions for their clinical application. We selected research articles from PubMed published within the last 5 years (from 2019), focusing on high‐impact journals and clinical trial data, and included a few key studies predating 2019. Considerations included the novelty of the research, sample size, experimental design, and data reliability. With advancements in single‐cell sequencing, CRISPR/Cas9 gene editing, and other cutting‐edge technologies, future MSC research will explore combination therapies and personalized treatments to provide more promising, safer treatments with reduced adverse reactions and enhanced therapeutic outcomes. These advances will improve kidney disease treatment methods, enhance patient quality of life, and maximize the benefits of MSC therapies.