Project description:Kidney stone disease causes significant morbidity and increases health care utilization. In this dataset, we applied a single-nucleus assay to renal papila samples in order to charachterize the cellular and molecular niches in patients with calcium oxalate (CaOx) stone disease and healthy subjects. In addition to identifying cell types important in papillary physiology, we characterize collecting duct cell subtypes and an undifferentiated epithelial cell type that was more prevalent in stone patients. Despite the focal nature of mineral deposition in nephrolithiasis, we uncover a global injury signature characterized by immune activation, oxidative stress and extracellular matrix remodeling. We also identify the association of MMP7 and MMP9 expression with stone disease and mineral deposition, respectively. MMP7 and MMP9 are significantly increased in the urine of patients with CaOx stone disease, and their levels correlate with disease activity. Our results define the spatial molecular landscape and specific pathways contributing to stone-mediated injury in the human papilla and identify associated urinary biomarkers.
2023-05-04 | GSE231569 | GEO
Project description:KiSMi Kidney stone patients - saliva samples
Project description:Kidney stone disease (KSD, also named renal calculi, nephrolithiasis, or urolithiasis) is a common urological disease entailing the formation of minerals and salts that form inside the urinary tract, frequently caused by diabetes and high blood pressure, hypertension, and monogenetic components in most patients. 10% of adults worldwide are affected by KSD, which incidence continues to be highly prevalent and increasing. For the identification of novel therapeutic targets in KSD to deal with this situation, we adopted high-throughput sequencing and mass spectrometry (MS) techniques in this study and carried out an integrative analysis of exosome proteome and DNA methylation data from blood samples of normal and KSD patients. Our study described the profiling of serum exosome and DNA methylation in blood from both normal individuals and those with Kidney Stone Disease (KSD), finding the overexpressed proteins and the demethylated DNA genes in KSD samples are related to immune reactions. The consistency of the results in proteomics and epigenetics supports the feasibility of the comprehensive strategy. Our understanding of the molecular landscape of KSD provides an opportunity for more information on the pathogenic mechanism, precise diagnosis, and treatment for KSD.
Project description:Clinical and animal studies have demonstrated the increasing evidence of oxidative stress in kidney stone disease. Recent findings have shown that the interactions between calcium oxalate (CaOx) crystals and renal tubular cells can promote many cellular events such as cell proliferation, cell death, cellular injury, mitochondrial dysfunction and inflammatory cascade. All of these cellular events are associated with oxidative stress and overproduction of free radicals and reactive oxygen species (ROS) such as superoxide and hydrogen peroxide in renal tubular cells. However, almost all of these references have shown that oxidative stress occurs after the causative crystals have been deposited in the kidney or exposed to renal tubular cells, whereas its primary role as the etiology remained unclear. In this study, we examined effects of oxidative modifications of urinary proteins on CaOx stone formation processes. Urinary proteins were modified by performic oxidation and the presence of oxidatively modified urinary proteins was verified, quantified and characterized by Oxyblot assay and tandem mass spectrometry (nanoLC-ESI-LTQ-Orbitrap-MS/MS). Subsequently, activities of oxidatively modified urinary proteins on CaOx stone formation processes were examined.
Project description:Kidney stone disease is influenced by multiple factors, including but not limited to age, gender, genetic background, hydration status, diet and drug. Regarding the gender, epidemiologic data across the world has shown that females at the reproductive age (15-49 years) have lower incidence/prevalence of kidney stone disease approximately 1.5-2.5 folds as compared to males at the same age. However, this gap is narrower in the postmenopausal age, whereas the postmenopausal females with higher serum estrogen levels are less likely to have kidney stones. Furthermore, female stone formers (patients with kidney stones) are associated with lower estrogen levels. Therefore, estrogen has been proposed to serve as the protective hormone against kidney stone disease. However, the precise mechanisms underlying such protective effects of estrogen remain unclear and require further investigations. This study thus investigated the effects of estradiol (which is the most prevalent and potent form of estrogen in females at the reproductive age) on cellular proteome of renal tubular cells using a proteomics approach.
Project description:<p>Genetic and environmental factors play an important role in the etiology of nephrolithiasis. This project will build on and extend our previous efforts (examining environmental risk factors for stone formation) by allowing us to study the risk of stone formation associated with specific genes and gene-environment interactions. We will take advantage of previously collected data in three large cohort studies: Nurses' Health Study I (n=121,000 women), Nurses' Health Study II (n=116,000 women), and Health Professionals Follow-up Study (n=51,000 men). Over a period of 17 to 26 years, information has been collected prospectively on important exposures including diet, family history, body size measures, past medical history, and medications. We have confirmed over 2000 incident cases of kidney stones in each cohort (DK59583, PI Curhan). Further, we have collected 24-hour urine samples from over 4100 stone formers and non-stone formers; the majority of participants have performed two collections. The primary objective of this project is to examine the association between single nucleotide polymorphisms and the 24-hour urinary excretion of stone promoters (calcium and oxalate) and a stone inhibitor (citrate). The secondary objective is to explore the impact of interactions between the genetic factors and dietary factors on 24-hour urinary excretion of relevant lithogenic factors. These findings should provide new insight into regulation of these important factors and also into novel approaches for prevention of stone formation.</p>
Project description:Comparison between renal papilla tissue with and without the presence of calcified Randall’s plaques, and between the papilla, medulla, and cortex regions from within a single recurrent stone forming kidney demonstrated that patterns of gene expression between the papilla, medulla, and cortex that distinguished these three regions from one another. Disease and function analysis of these gene sets demonstrated up-regulation of genes related to urinary/renal disorders, granulocyte response, vascular smooth muscle cell proliferation, dehydration, and renal calcification and down-regulation of genes related to carboxylic acid/ lipid/ fatty acid transport and urine osmolality.
Project description:Calcium oxalate stones account for over 80% of urinary stones, while the molecular mechanism of its formation is still not completely elucidated. The incidence of hyperoxaluria in calcium oxalate stone formation ranks only second to hypercalciuria. It plays an important role in the pathophysiological process of stone formation. We analyzed miRNA expression profiles between experimental hyperoxaluric rats and normal rats in order to find out the target genes and signaling pathways in the pathogenesis of hyperoxaluria.