Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation, fluid sheer stress, and inflammatory pathways in obesity-related glomerulopathy.

Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.

IGF2BP3-stabilized CAMK1 regulates the mitochondrial dynamics of renal tubule to alleviate diabetic nephropathy.

BACKGROUND: CAMK1 has been shown to be involved in human disease progression via regulating mitochondrial dynamics. However, whether CAMK1 mediates mitochondrial dynamics to regulate diabetic nephropathy (DN) process remains unclear. METHODS: Mice were injected with streptozotocin (STZ) to mimic diabetic mice models in vivo, and mice with proximal tubule-specific knockout of CAMK1 (CAMK1-KO) were generated. HK-2 cells were treated with high-glucose (HG) to mimic DN cell model in vitro. Histopathological analysis was performed to confirm kidney injury in mice. ROS production and apoptosis were assessed by DHE staining and TUNEL staining. Mitochondria morphology was observed and analyzed by electron microscopy. Mitochondrial membrane potential was detected by JC-1 staining, and cell proliferation was measured by EdU assay. The mRNA and protein expression were examined by qRT-PCR, western blot and immunostaining. RNA interaction was confirmed by RIP assay and dual-luciferase reporter assay. The mRNA stability was tested by actinomycin D treatment, and m6A level was examined by MeRIP assay. RESULTS: CAMK1 was reduced in DN patients and STZ-induced diabetic mice. Conditional deletion of CAMK1 aggravated kidney injury and promoted mitochondrial fission in diabetic mice. CAMK1 overexpression inhibited mitochondrial fission to alleviate HG-induced HK-2 cell apoptosis. IGF2BP3 promoted the stability of CAMK1 mRNA by m6A modification. IGF2BP3 inhibited mitochondrial fission to repress cell apoptosis in vitro and kidney injury in vivo by increasing CAMK1 expression. CONCLUSION: IGF2BP3-mediated CAMK1 mRNA stability alleviated DN progression by inhibiting mitochondria fission.

Targeting Renal Proximal Tubule Cells in Obesity-Related Glomerulopathy.

As a metabolic disorder, obesity can cause secondary kidney damage, which is called obesity-related glomerulopathy (ORG). As the incidence of obesity increases worldwide, so does the incidence of end-stage renal disease (ESRD) caused by ORGs. However, there is still a lack of effective strategies to prevent and delay the occurrence and development of ORG. Therefore, a deeper understanding and elaboration of the pathogenesis of ORG is conducive to the development of therapeutic drugs for ORG. Here, we review the characteristics of pathological lesions of ORG and describe the roles of lipid metabolism disorders and mitochondrial oxidative stress in the development of ORG. Finally, we summarize the current available drugs or compounds for the treatment of ORG and suggested that ameliorating renal lipid metabolism and mitochondrial function may be potential therapeutic targets for ORG.

Biopolymer-Based Nanosystems: Potential Novel Carriers for Kidney Drug Delivery.

Kidney disease has become a serious public health problem throughout the world, and its treatment and management constitute a huge global economic burden. Currently, the main clinical treatments are not sufficient to cure kidney diseases. During its development, nanotechnology has shown unprecedented potential for application to kidney diseases. However, nanotechnology has disadvantages such as high cost and poor bioavailability. In contrast, biopolymers are not only widely available but also highly bioavailable. Therefore, biopolymer-based nanosystems offer new promising solutions for the treatment of kidney diseases. This paper reviews the biopolymer-based nanosystems that have been used for renal diseases and describes strategies for the specific, targeted delivery of drugs to the kidney as well as the physicochemical properties of the nanoparticles that affect the targeting success.

Targeted drug delivery strategy: a bridge to the therapy of diabetic kidney disease.

Diabetic kidney disease (DKD) is the main complication in diabetes mellitus (DM) and the main cause of end-stage kidney disease worldwide. However, sodium glucose cotransporter 2 (SGLT2) inhibition, glucagon-like peptide-1 (GLP-1) receptor agonist, mineralocorticoid receptor antagonists and endothelin receptor A inhibition have yielded promising effects in DKD, a great part of patients inevitably continue to progress to uremia. Newly effective therapeutic options are urgently needed to postpone DKD progression. Recently, accumulating evidence suggests that targeted drug delivery strategies, such as macromolecular carriers, nanoparticles, liposomes and so on, can enhance the drug efficacy and reduce the undesired side effects, which will be a milestone treatment in the management of DKD. The aim of this article is to summarize the current knowledge of targeted drug delivery strategies and select the optimal renal targeting strategy to provide new therapies for DKD.

Renal Proximal Tubular Cells: A New Site for Targeted Delivery Therapy of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD) worldwide. A significant number of drugs have been clinically investigated for the treatment of DKD. However, a large proportion of patients still develop end-stage kidney disease unstoppably. As a result, new effective therapies are urgently needed to slow down the progression of DKD. Recently, there is increasing evidence that targeted drug delivery strategies such as large molecule carriers, small molecule prodrugs, and nanoparticles can improve drug efficacy and reduce adverse side effects. There is no doubt that targeted drug delivery strategies have epoch-making significance and great application prospects for the treatment of DKD. In addition, the proximal tubule plays a very critical role in the progression of DKD. Consequently, the purpose of this paper is to summarize the current understanding of proximal tubule cell-targeted therapy, screen for optimal targeting strategies, and find new therapeutic approaches for the treatment of DKD.

The Loss of Mitochondrial Quality Control in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.

RvD1 Attenuated Susceptibility to Ischemic AKI in Diabetes by Downregulating Nuclear Factor-κ B Signal and Inhibiting Apoptosis.

BACKGROUND: Acute kidney injury (AKI), when occurring in diabetic kidney disease (DKD), is known to be more severe and difficult to recover from. Inflammation and apoptosis may contribute to the heightened sensitivity of, and non-recovery from, AKI in patients with DKD. Resolvin D1 (RvD1) is a potent lipid mediator which can inhibit the inflammatory response and apoptosis in many diseases. However, it has been reported that the RvD1 levels were decreased in diabetes, which may explain why DKD is more susceptible to AKI. METHODS: For animal experiments, diabetic nephropathy (DN) mice were induced by streptozotocin (STZ) injection intraperitoneally. Renal ischemia-reperfusion was used to induce AKI. Blood urea nitrogen (BUN) and serum creatinine were determined using commercial kits to indicate renal function. Renal apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Real-time polymerase chain reaction (PCR) was used to detect the marker of inflammatory response. Western blot was used to detect the expression of nuclear factor-κB (NF-κB)-related proteins. For clinical study, 12 cases diagnosed with DKD were enrolled in this study, and an equal number of non-diabetic renal disease patients (NDKD) were recruited as a control group. The serum RvD1 in DKD or NDKD patients were detected through an ELISA kit. RESULTS: In clinical study, we found that the serum RvD1 levels were decreased in DKD patients compared to those in NDKD patients. Decreased serum RvD1 levels were responsible for the susceptibility to ischemic AKI in DKD patients. In animal experiments, both the serum RvD1 and renal ALX levels were downregulated. RvD1 treatment could ameliorate renal function and histological damage after ischemic injury in DN mice. RvD1 treatment also could inhibit the inflammatory response. Di-tert-butyl dicarbonate (BOC-2) treatment could deteriorate renal function and histological damage after ischemic injury in non-diabetic mice. RvD1 could inhibit the NF-κB activation and suppress inflammatory response mainly by inhibiting NF-κB signaling. CONCLUSION: RvD1 attenuated susceptibility to ischemic AKI in diabetes by downregulating NF-κB signaling and inhibiting apoptosis. Downregulated serum RvD1 levels could be the crucial factor for susceptibility to ischemic AKI in diabetes.

Epigenetic Histone Modifications in the Pathogenesis of Diabetic Kidney Disease.

Diabetic kidney disease (DKD), as the main complication of diabetes mellitus, is the primary cause of the end-stage renal disease (ESRD) and the most common chronic kidney disease. Overall, 30-40% of patients with type 1 and type 2 diabetes eventually develop DKD. Although some diabetes patients have intensified glycemic control, they still develop diabetic kidney disease. Current treatment methods can alleviate but do not markedly halt disease development, resulting in renal failure and severe complications, even contributing to elevated morbidity and mortality rates. DKD is a disease with interactions of genes and the environment. Emerging evidence indicates that DKD-associated key genes are also regulated by the epigenetic mechanism. Recently, increasing researches involving cells and experimental animals demonstrated that histone post-translational modifications can mediate gene expression, which correlated with diabetic kidney disease. Novel therapeutic strategies for epigenetic events could be beneficial for the early detection and treatment of DKD to prevent it from developing into end-stage renal disease (ESRD). In this review, we discuss prior findings in the field of histone modifications in DKD, especially histone acetylation and histone methylation. We then focus on recent developments in histone acetylation and methylation involved in the pathogenesis of DKD.