Li, Xiaogang

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth. However, considering the complexity of epigenetic mechanisms and the broad range of alterations of epigenetic components in ADPKD, identifying more specific epigenetic factors and understanding how they are mechanistically linked to promote cyst growth is relevant for the development of treatment for ADPKD. Here, we find that the histone methyltransferase SMYD3, which activates gene transcription via histone H3 lysine 4 trimethylation (H3K4me3), is upregulated in PKD1 mutant mouse and human ADPKD kidneys. Genetic knockout of SMYD3 in a PKD1 knockout mouse model delayed cyst growth and improved kidney function compared with PKD1 single knockout mouse kidneys. Immunostaining and Western blot assays indicated that SMYD3 regulated PKD1-associated signaling pathways associated with proliferation, apoptosis, and cell cycle effectors in PKD1 mutant renal epithelial cells and tissues. In addition, we found that SMYD3 localized to the centrosome and regulated mitosis and cytokinesis via methylation of α-tubulin at lysine 40. In addition, SMYD3 regulated primary cilia assembly in PKD1 mutant mouse kidneys. In summary, our results demonstrate that overexpression of SMYD3 contributes to cyst progression and suggests targeting SMYD3 as a potential therapeutic strategy for ADPKD.

Genetic abnormalities play a crucial role in the development of neurodegenerative disorders (NDDs). Genetic exploration has indeed contributed to unraveling the molecular complexities responsible for the etiology and progression of various NDDs. The intricate nature of rare and common variants in NDDs contributes to a limited understanding of the genetic risk factors associated with them. Advancements in next-generation sequencing have made whole-genome sequencing and whole-exome sequencing possible, allowing the identification of rare variants with substantial effects, and improving the understanding of both Mendelian and complex neurological conditions. The resurgence of gene therapy holds the promise of targeting the etiology of diseases and ensuring a sustained correction. This approach is particularly enticing for neurodegenerative diseases, where traditional pharmacological methods have fallen short. In the context of our exploration of the genetic epidemiology of the three most prevalent NDDs—amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease, our primary goal is to underscore the progress made in the development of next-generation sequencing. This progress aims to enhance our understanding of the disease mechanisms and explore gene-based therapies for NDDs. Throughout this review, we focus on genetic variations, methodologies for their identification, the associated pathophysiology, and the promising potential of gene therapy. Ultimately, our objective is to provide a comprehensive and forward-looking perspective on the emerging research arena of NDDs.

In the era of precision medicine, liquid biopsy techniques, especially the use of urine analysis, represent a paradigm shift in the identification of biomarkers, with considerable implications for clinical practice in the field of nephrology. In kidney diseases, the use of this non-invasive tool to identify specific and sensitive biomarkers other than plasma creatinine and the glomerular filtration rate is becoming crucial for the diagnosis and assessment of a patient’s condition. In recent years, studies have drawn attention to the importance of exosomes for diagnostic and therapeutic purposes in kidney diseases. Exosomes are nano-sized extracellular vesicles with a lipid bilayer structure, composed of a variety of biologically active substances. In the context of kidney diseases, studies have demonstrated that exosomes are valuable carriers of information and are delivery vectors, rendering them appealing candidates as biomarkers and drug delivery vehicles with beneficial therapeutic outcomes for kidney diseases. This review summarizes the applications of exosomes in kidney diseases, emphasizing the current biomarkers of renal diseases identified from urinary exosomes and the therapeutic applications of exosomes with reference to drug delivery and immunomodulation. Finally, we discuss the challenges encountered when using exosomes for therapeutic purposes and how these may affect its clinical applications.

Contrast-induced acute kidney injury (CI−AKI) is manifested by an abrupt decline in kidney function as a consequence of intravascular exposure to contrast media. With the increased applicability of medical imaging and interventional procedures that utilize contrast media for clinical diagnosis, CI−AKI is becoming the leading cause of renal dysfunction. The pathophysiological mechanism associated with CI−AKI involves renal medullary hypoxia, the direct toxicity of contrast agents, oxidative stress, apoptosis, inflammation, and epigenetic regulation. To date, there is no effective therapy for CI−AKI, except for the development of strategies that could reduce the toxicity profiles of contrast media. While most of these strategies have failed, evidence has shown that the proper use of personalized hydration, contrast medium, and high-dose statins may reduce the occurrence of CI−AKI. However, adequate risk predication and attempts to develop preventive strategies can be considered as the key determinants that can help eliminate CI−AKI. Additionally, a deeper understanding of the pathophysiological mechanism of CI−AKI is crucial to uncover molecular targets for the prevention of CI−AKI. This review has taken a step further to solidify the current known molecular mechanisms of CI−AKI and elaborate the biomarkers that are used to detect early-stage CI−AKI. On this foundation, this review will analyze the molecular targets relating to apoptosis, inflammation, oxidative stress, and epigenetics, and, thus, provide a strong rationale for therapeutic intervention in the prevention of CI−AKI.

In recent years, the launch of clinical-grade exosomes is rising expeditiously, as they represent a new powerful approach for the delivery of advanced therapies and for diagnostic purposes for various diseases. Exosomes are membrane-bound extracellular vesicles that can act as biological messengers between cells, in the context of health and disease. In comparison to several lab-based drug carriers, exosome exhibits high stability, accommodates diverse cargo loads, elicits low immunogenicity and toxicity, and therefore manifests tremendous perspectives in the development of therapeutics. The efforts made to spur exosomes in drugging the untreatable targets are encouraging. Currently, T helper (Th) 17 cells are considered the most prominent factor in the establishment of autoimmunity and several genetic disorders. Current reports have indicated the importance of targeting the development of Th17 cells and the secretion of its paracrine molecule, interleukin (IL)-17. However, the present-day targeted approaches exhibit drawbacks, such as high cost of production, rapid transformation, poor bioavailability, and importantly, causing opportunistic infections that ultimately hamper their clinical applications. To overcome this hurdle, the potential use of exosomes as vectors seem to be a promising approach for Th17 cell-targeted therapies. With this standpoint, this review discusses this new concept by providing a snapshot of exosome biogenesis, summarizes the current clinical trials of exosomes in several diseases, analyzes the prospect of exosomes as an established drug carrier and delineates the present challenges, with an emphasis on their practical applications in targeting Th17 cells in diseases. We further decode the possible future scope of exosome bioengineering for targeted drug delivery against Th17 cells and its catastrophe.

ADPKD is a genetic disorder with a molecular complexity that remains poorly understood. In this study, we sampled renal cells to construct a comprehensive and spatiotemporally resolved gene expression atlas in whole Pkd1 mutant polycystic mouse kidneys at single-cell resolution. We characterized cell diversity and identified novel collecting duct (CD) cell subtypes in cystic kidneys. We further found that CD cells appear to take different cell fate trajectories, and the first and the most important step might take place around day 14 in Pkd1 homozygous kidneys. After that day, increased numbers of CD cells showed highly proliferative and fibrotic characteristics, as detected in later-stage Pkd1 homozygous kidneys, both of which should contribute to cyst growth and renal fibrosis. With a newly developed modeling algorithm, called CellChat Explorer, we identify cell-to-cell communication networks mediated by the ligand receptor, such as MIF-CD44/CD74, in cystic kidneys, and confirm them via the expression patterns of ligands and receptors in four major cell types, which addresses the key question as to whether and how Pkd1 mutant renal epithelial cells affect their neighboring cells. The allele-specific gene expression profiles show that the secretion of cytokines by Pkd1 mutant epithelial cells may affect the gene expression profiles in recipient cells via epigenetic mechanisms, and vice versa. This study can be used to drive precision therapeutic targeting of ADPKD.