Treatment Of Diabetic Kidney Disease Research Articles

Discussion on the treatment of diabetic kidney disease based on the "gut-fat-kidney" axis.

Diabetic kidney disease is the main cause of end-stage renal disease, and its prevention and treatment are still a major clinical problem. The human intestine has a complex flora of hundreds of millions of microorganisms, and intestinal microorganisms, and their derivatives are closely related to renal inflammatory response, immune response, and material metabolism. Brown adipose tissue is the main part of adaptive thermogenesis. Recent studies have shown that activating brown fat by regulating intestinal flora has good curative effects in diabetic kidney disease-related diseases. As an emerging medical concept, the "gut-fat-kidney" axis has received increasing attention in diabetic kidney disease and related diseases. However, the specific mechanism involved needs further study. A new theoretical basis for the prevention and treatment of diabetic kidney disease is presented in this article, based on the "gut-fat-kidney" axis.

A novel role of peroxiredoxin 2 in diabetic kidney disease progression by activating the classically activated macrophages.

Diabetic kidney disease (DKD) is the main cause of deaths due to diabetes mellitus (DM). Due to the complexity of its onset, it is difficult to achieve accurate prevention and treatment. The classically activated macrophage (M1) polarization is a crucial proinflammatory mechanism of DKD, while the interaction and cascade effects of oxidative stress and inflammatory response remain to be elucidated. A urine proteomic analysis of patients with DM indicated that peroxiredoxin 2 (PRDX2) had the higher abundance in DKD. We recently found that PRDX of parasitic protozoa Entamoeba histolytica, which was similar to human PRDX2 in amino acid sequence and spatial structure, could activate the inflammatory response of macrophages through toll-like receptor 4 (TLR4). Hence, our study was designed to explore the role of PRDX2 in chronic inflammation during DKD. Combined with in vivo and in vitro experiments, results showed that the PRDX2 was positively correlated with DKD progression and upregulated by high glucose or recombinant tumor necrosis factor-α in renal tubular epithelial cells; Besides, recombinant PRDX2 could promote M1 polarization of macrophages, and enhance the migration as well as phagocytic ability of macrophages through TLR4. In summary, our study has explored the novel role of PRDX2 in DKD to provide a basis for further research on the diagnosis and treatment of DKD.

Correction of the clinical course of non-alcoholic steatohepatitis and diabetic kidney disease in patients with type 2 diabetes

Background. The relevance of finding optimal methods to treat patients with a comorbid non-alcoholic steatohepatitis (NASH) that developed against the background of type 2 diabetes mellitus (T2DM) is due to the fact that these diseases have a number of common cause-and-effect mechanisms, and if diabetic kidney disease (DKD) develops, also mutual burden mechanisms. The purpose of the study was to find out the possible influence of a combination of metformin, rosuvastatin, essential phospholipids and quercetin on the clinical course of non-alcoholic steatohepatitis, diabetic kidney disease, type 2 diabetes mellitus, as well as on the state of the blood lipids, parameters of carbohydrate metabolism compensation, the degree of insulin resistance, which are factors for the progression of NASH and diabetic kidney disease. Materials and methods. Studies were conducted on the dynamics of treatment in 60 patients with NASH, T2DM and DKD stage I–III: 48 (80.0 %) of them had mild NASH, and 12 (20.0 %) had moderate NASH. A comorbid disease in 100 % of patients was moderate type 2 diabetes: 15 (25.0 %) people were diagnosed with diabetes in the stage of compensation, 45 (75.0 %) had subcompensated disease. Results. The positive effect of quercetin was noted by us in relation to the content of low-density lipoprotein cholesterol in the blood that was increased by 1.8 times (p < 0.05) before the treatment: a decrease after it was 1.7 times (p < 0.05) in group 2 and 1.3 times (p < 0.05) in group 1. Comprehensive therapy with the inclusion of quercetin contributed to a probable increase in anti-atherogenic high-density lipoprotein (by 1.3 times, p < 0.05) with the normalization of the indicator after the treatment, while traditional therapy in this contingent did not lead to any probable changes. Conclusions. The combination therapy for type 2 diabetes mellitus and NASH with the addition of quercetin contributed to the elimination of the main clinical and laboratory symptoms of NASH exacerbation, a probable reduction in the liver inflammation (a decrease in markers of cytolysis, mesenchymal inflammation), reversal of hepatic steatosis due to the optimization of cholesterol and triacylglycerols in the blood, a probable increase in high-density lipoproteins, normalization of glycemia, reduction of insulinemia, a decrease in the degree of insulin resistance. The effectiveness of treatment for DKD was also increased: the rate of proteinuria and the degree of hypercreatinemia decreased, and the glomerular filtration rate increased.

Inhibition of SGLT2 protects podocytes in diabetic kidney disease by rebalancing mitochondria-associated endoplasmic reticulum membranes

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors have changed the therapeutic landscape for diabetic kidney disease (DKD) patients, but their underlying mechanisms are complicated and not fully understood. Mitochondria-associated endoplasmic reticulum membranes (MAMs), the dynamic contact sites between mitochondria and the endoplasmic reticulum (ER), serve as intracellular platforms important for regulating cellular fate and function. This study explored the roles and mechanisms of SGLT2 inhibitors in regulating MAMs formation in diabetic podocytes.MethodsWe assessed MAMs formation in podocytes from DKD patients’ renal biopsy samples and induced an increase in MAMs formation in cultured human podocytes by transfecting OMM-ER linker plasmid to investigate the effects of MAMs imbalance on podocyte injury. Empagliflozin-treated diabetic mice and podocyte-specific SGLT2 knockout diabetic mice (diabetic states were induced by streptozotocin and a high-fat diet), empagliflozin-treated podocytes, SGLT2-downregulated podocytes, and SGLT2-overexpressing podocytes were used to investigate the effects and mechanisms of SGLT2 inhibitors on MAMs formation in diabetic podocytes.ResultsMAMs were increased in podocytes and were associated with renal dysfunction in DKD patients. Increased MAMs aggravated HG-induced podocyte injury. The expression of SGLT2 was increased in diabetic podocytes. In addition, empagliflozin-treatment and podocyte-specific SGLT2 knockout attenuated MAMs formation and podocyte injury in diabetic mice. Empagliflozin treatment and SGLT2 knockdown decreased podocyte MAMs formation by activating the AMP-activated protein kinase (AMPK) pathway, while SGLT2 overexpression had the opposite effect.ConclusionsInhibition of SGLT2 attenuates MAMs imbalance in diabetic podocytes by activating the AMPK pathway. This study expands our knowledge of the roles of SGLT2 inhibitors in improving DKD podocyte injury and provides new insights into DKD treatment.

Explaining the Mechanism of Diabetic Kidney Disease from Macro and Micro Viewpoints

Diabetic kidney disease is one of the major microvascular complications of diabetes mellitus. This paper summarizes the Chinese medicine theories such as "Zangxiang" and "qi, blood and fluid", and combs through the literature related to the identification and treatment of diabetic kidney disease from a microscopic point of view, to elaborate the clinical symptoms of diabetic kidney disease and the pathomechanisms of renal pathology from a macroscopic and a microscopic point of view. At the same time, we analyze the Chinese medicines used in the TCM treatment of diabetic kidney disease in the literature in the past 5 years, and discuss the internal organs related to the pathogenesis of diabetic kidney disease.

Leech granules inhibit ferroptosis and alleviate renal injury in mice with diabetic kidney disease

Ethnopharmacological relevanceThe underlying mechanisms of diabetic kidney disease (DKD) and effective treatment strategies remain unclear. DKD progression is closely associated with abnormal iron metabolism and ferroptosis in vivo. Leeches, used in traditional Chinese medicine for promoting blood circulation and resolving blood stasis, are utilized to treat diabetes and its associated complications. Leeches effectively antagonize oxidative stress injury and exert protective effects on renal function. However, whether leeches can inhibit ferroptosis by modulating oxidative stress and iron metabolism remains unclear. Aim of the studyTo investigate the therapeutic potential of leech granules in DKD and, specifically, their effects on ferroptosis. Materials and methodsWe used a mouse model of DKD. The mice were treated with leech granules via gavage. Component identification and analysis of leech granules were performed using UPLC-MS, and efficacy was assessed by histopathology and analysis of blood glucose, lipids, and renal function. Additionally, the pharmacological mechanisms of leech granules were explored via proteomics, immunohistochemical staining, western blotting, and cell culture. ResultsProteomic analysis showed that iron metabolism was dysregulated and ferroptosis increased in DKD mice. Leech granules significantly reduced iron accumulation and renal pathological damage, decreased ROS levels, upregulated GSH levels, and inhibited ferroptosis in the kidneys of DKD mice. Furthermore, in vitro cellular experiments demonstrated that leech granules could inhibit erastin-induced ferroptosis and protect renal cells. ConclusionsThe regulation of renal iron metabolism and inhibition of ferroptosis mediates the therapeutic effect of leech granules on DKD. Leech granules represent a promising approach for DKD treatment.

Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease.

Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.

C/EBPα-mediated ACSL4-dependent ferroptosis exacerbates tubular injury in diabetic kidney disease

Diabetic kidney disease (DKD) is a prevalent and debilitating complication of diabetes characterized by progressive renal function decline and a lack of effective treatment options. Here, we investigated the role of the transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) in DKD pathogenesis. Analysis of renal biopsy samples revealed increased C/EBPα expression in patients with DKD. Using RNA sequencing and proteomics, we explored the mechanisms through which the C/EBPα contributes to DKD. Our findings demonstrated that C/EBPα exacerbated tubular injury by promoting acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. We identified that C/EBPα upregulated ACSL4 expression by binding to its transcription regulatory sequence (TRS), leading to elevated lipid peroxidation and ferroptosis. Furthermore, inhibition or genetic ablation of C/EBPα attenuated ferroptosis and mitigated tubular injury in DKD. These results highlighted the C/EBPα-ACSL4-ferroptosis pathway as a promising therapeutic target for DKD treatment.

Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation

Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.

Identifying Key Genes and Mechanisms in Active Vitamin D Treatment for Diabetic Kidney Disease

Identifying Key Genes and Mechanisms in Active Vitamin D Treatment for Diabetic Kidney Disease

Mesenchymal Stem Cell Therapy: Therapeutic Opportunities and Challenges for Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), which severely affects the quality of patients' lives. However, the current therapeutic approaches can only postpone its progression to ESRD. It is therefore imperative to develop a novel therapeutic strategy for renal injury in DKD, with the objective of restoring renal function and reversing the process of ESRD. In recent years, the potential of mesenchymal stem cell (MSC) therapy for DKD has garnered increasing attention within the scientific community. Preclinical research on MSC therapy has yielded promising results, and the safety of MSC treatment in vivo has been substantiated in clinical studies. An increasing body of evidence suggests that MSC therapy has significant potential for the treatment of DKD. This article reviews the existing research on MSCs and their derived exosomes in treating DKD and analyzes the underlying mechanism of MSC-based therapy for DKD. Additionally, we discuss the potential of combining MSC therapy with conventional pharmacological treatments, along with the constraints and prospects of MSC therapy for DKD. We hope this review can provide a precise and comprehensive understanding of MSCs for the treatment of DKD.

Huaiqihuang (HQH) protects podocytes from high glucose-induced apoptosis and inflammation response by regulating PI3K/AKT/mTOR pathway

Diabetic kidney disease (DKD) is one of the common microvascular complications of diabetes, and there are still lack of effective treatments. Huaiqihuang (HQH) is a kind of traditional Chinese medicine mixed preparation, which is mainly made of Trametes robiniophila Murr, Fructus Lycii, and Polygonatum sibiricumhas. It has been shown to be effective in the treatment of DKD, but the specific mechanism has not been fully elucidated. Our results showed that HQH increased the protein expressions of synaptopodin, podocin, WT-1, and Bcl-2, decreased the protein expressions of Bax and cleaved-casepase-3, and activated the NF-ĸB and PI3K/AKT/mTOR pathway in MPC5 cells exposed to high-glucose (HG). Real-time PCR results showed that HQH reduced the mRNA expression of TNF-α, IL-1β, MCP-1, and IL-6. In conclusion, our results showed that HQH may attenuate podocyte injury by inhibiting MPC5 cell apoptosis induced by HG and NF-κB-mediated inflammation response through activation of the PI3K/AKT/mTOR pathway.

CXCL5 inhibition improves kidney function by protecting renal tubular epithelial cells in diabetic kidney disease

Inflammation is one of exacerbating factors of diabetic kidney disease (DKD). Upregulated CXCL5 is found in clinical and experimental diabetes studies. This study aimed to investigate the impact and mechanism of CXCL5 on DKD. DKD patients with different levels of urine albumin-to-creatinine ratio were enrolled. Leprdb/db mice and CXCL5-knockout diabetic mice were used as mouse models for DKD. Human renal tubular epithelial cells were used for in vitro experiments. Circulating CXCL5 were increased in DKD patients compared to the non-DKD subjects. CXCL5 inhibition through CXCL5-neutralizing antibodies or genetic knockout improved kidney function and ameliorated tubular injury and renal fibrosis. In high-glucose-stimulated tubular epithelial cells, administration of CXCL5-neutralizing antibodies or siRNA resulted in reduced phospho-JNK/c-JUN/p65 and the downstream inflammatory, fibrotic, and apoptotic protein expressions. Administration of CXCR2 and JNK inhibitors impeded the CXCL5-induced tubular epithelial cell damages. In conclusion, these findings indicated that anti-CXCL5 strategies may be potential treatments for DKD.

Predicting prospective therapeutic targets of Bombyx batryticatus for managing diabetic kidney disease through network pharmacology analysis.

We conducted network pharmacology and molecular docking analyses, and executed in vitro experiments to assess the mechanisms and prospective targets associated with the bioactive components of Bombyx batryticatus in the treatment of diabetic kidney disease (DKD). The bioactive components and potential targets of B batryticatus were sourced from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Using 5 disease databases, we conducted a comprehensive screening of potential disease targets specifically associated with DKD. Common targets shared between the bioactive components and disease targets were identified through the use of the R package, and subsequently, a protein-protein interaction network was established using data from the STRING database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses pertaining to the identified common targets were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Molecular docking simulations involving the bioactive components and their corresponding targets were modeled through AutoDock Vina and Pymol. Finally, to corroborate and validate these findings, experimental assays at the cellular level were conducted. Six bioactive compounds and 142 associated targets were identified for B batryticatus. Among the 796 disease targets associated with DKD, 56 targets were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed the involvement of these shared targets in diverse biological processes and signaling pathways, notably the PI3K-Akt signaling pathway. Molecular docking analyses indicated a favorable binding interaction between quercetin, the principal bioactive compound in B batryticatus, and RAC-alpha serine/threonine-protein kinase. Subsequently, in vitro experiments substantiated the inhibitory effect of quercetin on the phosphorylation level of PI3K and Akt. The present study provides theoretical evidence for a comprehensive exploration of the mechanisms and molecular targets by which B batryticatus imparts protective effects against DKD.

Angiopoietin-like 4 is a potential biomarker for diabetic kidney disease in type 2 diabetes patients.

The association between serum angiopoietin-like 4 (ANGPTL4) levels and the severity of diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus remains unclear. A total of 1,115 type 2 diabetes mellitus patients were analyzed in this cross-sectional study. DKD index included DKD stages defined by estimated glomerular filtration rate, the albuminuria grades and DKD risk management grades. Serum levels of ANGPTL4 and other biomarkers were detected. Multivariable-adjusted linear and logistic analyses were used to study the association between ANGPTL4 and DKD. The protein levels of ANGPTL4 were assessed in the kidney. Renal tubular cells were stimulated with glucose to study ANGPTL4 expression. Compared with the participants in the third or fourth quantile of ANGPTL4, those in the first or second quantile of ANGPTL4 were younger, with lower glycated hemoglobin, triglycerides and urinary albumin creatinine ratio (all P < 0.05). There was a negative nonlinear relationship between ANGPTL4 and estimated glomerular filtration rate in type 2 diabetes mellitus patients. One standard deviation increased serum ANGPTL4 levels, the odds ratio of having DKD was 1.40 (95% confidence interval 1.08-1.80). The mediation analysis showed that triglycerides did not mediate the association between ANGPTL4 and DKD. Furthermore, ANGPTL4 could be the strongest among multiple panels of biomarkers in its association of DKD. Compared with mice at 8 weeks-of-age, db/db mice at 18 weeks-of-age had increased ANGPTL4 expression in glomeruli and tubular segments. In vitro, glucose could stimulate ANGPTL4 expression in tubular cells in a dose-dependent manner. ANGPTL4 could be a potential marker and therapeutic target for DKD treatment.

Effectiveness and safety of finerenone in diabetic kidney disease patients: a real-world observational study from China

Aims Finerenone has been approved for treating diabetic kidney disease (DKD) with reducing cardiorenal risk. Real-world data on finerenone treatment for the management of DKD are presently lacking. This study aimed to investigate the effect of finerenone on the renal parameters of the Chinese DKD population in the real-world medical setting for the first time, especially in combination with renin–angiotensin system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). Methods Forty-two DKD patients were selected and completed a 6-month finerenone treatment. Renal parameters and adverse effects were collected at every visit. Results The median urine albumin-to-creatinine ratio (UACR) was 1426.11 (755.42, 3638.23) mg/g. Among them, the proportion of patients with a UACR of 300–5000 mg/g was 76.2%, and the proportion of patients with a UACR of >5000 mg/g was 14.3%. The median estimated glomerular filtration rate (eGFR) was 54.50 (34.16, 81.73) mL/min/1.73 m2. Finerenone decreased the UACR significantly throughout the study period (p < .05). The maximal decline of UACR at month 6 was 73%. Moreover, the proportion of patients with a 30% or greater reduction in UACR was 68.42% in month 6. There was a smaller decline (9–11%) in the eGFR after initiating finerenone (p > .05). One patient each discontinued finerenone due to hyperkalemia (2.4%) and acute kidney injury (2.4%). No patient reported hypotension, breast pain, and gynecomastia. Conclusions This study from China first demonstrated finerenone decreased UACR with manageable safety in real-world DKD treatment. A triple regimen of RASi, SGLT2i, and finerenone may be a promising treatment strategy for lowering albuminuria and reducing hyperkalemia risk in advanced DKD patients.

Compositional Analysis and Network Pharmacological Strategy for the Treatment of Diabetic Kidney Disease by Shengjiang Powder Based on UHPLC-Q-TOF-MS

Objective: Shengjiang Powder (SJP) is a traditional Chinese medicine compound formula commonly used in the treatment of diabetic kidney disease (DKD). However, its material basis and mechanism of action are still unclear. Methods: In this study, the aqueous extract of SJP was obtained by aqueous decoction method, and the in vivo and in vitro constituents of SJP were analysed by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), and a network pharmacological strategy was established in conjunction with molecular docking in order to investigate the mechanism of action of SJP in the treatment of DKD. Results: The results identified 162 components, of which 28 could be absorbed into the blood and exert therapeutic effects in vivo. The main active ingredients were CT-1, CT-2, CT-7, BJC-2, and BJC-5, and the main targets in vivo were related to AKT1, MAPK1, MAPK3, MAPK8, and MAPK14, which could exert their therapeutic effects through the PI3K-Akt signaling pathway, Insulin resistance, and AGE-RAGE signaling pathway in diabetic complications, etc Conclusion: The present study adopts a comprehensive analytical strategy to reveal the pharmacodynamic material basis and mechanism of action of SJP in the treatment of DKD, and to provide a scientific basis for its clinical application.

The mineralocorticoid receptor in diabetic kidney disease.

Diabetes mellitus is one of the leading causes of chronic kidney disease and its progression to end-stage kidney disease (ESKD). Diabetic kidney disease (DKD) is characterized by glomerular hypertrophy, hyperfiltration, inflammation, and the onset of albuminuria, together with a progressive reduction in glomerular filtration rate. This progression is further accompanied by tubulointerstitial inflammation and fibrosis. Factors such as genetic predisposition, epigenetic modifications, metabolic derangements, hemodynamic alterations, inflammation, and inappropriate renin-angiotensin-aldosterone system (RAAS) activity contribute to the onset and progression of DKD. In this context, decades of work have focused on glycemic and blood pressure reduction strategies, especially targeting the RAAS to slow disease progression. Although much of the work has focused on targeting angiotensin II, emerging data support that the mineralocorticoid receptor (MR) is integral in the development and progression of DKD. Molecular mechanisms linked to the underlying pathophysiological changes derived from MR activation include vascular endothelial and epithelial cell responses to oxidative stress and inflammation. These responses lead to alterations in the microcirculatory environment, the abnormal release of extracellular vesicles, gut dysbiosis, epithelial-mesenchymal transition, and kidney fibrosis. Herein, we present recent experimental and clinical evidence on the MR in DKD onset and progress along with new MR-based strategies for the treatment and prevention of DKD.

Urine complement proteins are associated with kidney disease progression of type 2 diabetes in Korean and American cohorts.

Mechanisms of progression of diabetic kidney disease (DKD) are not completely understood. This study uses untargeted and targeted mass spectrometry-based proteomics in two independent cohorts on two continents to decipher the mechanisms of DKD in patients with type 2 diabetes. We conducted untargeted mass spectrometry on urine samples collected at the time of kidney biopsy from Korean patients with type 2 diabetes and biopsy-proven diabetic nephropathy at Seoul National University Hospital (SNUH-DN cohort; n = 64). These findings were validated using targeted mass spectrometry in urine samples from a Chronic Renal Insufficiency Cohort subgroup with type 2 diabetes and DKD (CRIC-T2D; n = 282). Urinary biomarkers/pathways associated with kidney disease progression (doubling of serum creatinine, ≥50% decrease in estimated glomerular filtration rates, or the development of end-stage kidney disease) were identified. SNUH-DN patients had an estimated glomerular filtration rate (eGFR) of 55 mL/min/1.73 m 2 (interquartile range [IQR], 44-75) and random urine protein-to-creatinine ratio of 3.1 g/g (IQR, 1.7-7.0). Urine proteins clustered into two groups, with cluster 2 having a 4.6-fold greater hazard (95% confidence interval [CI], 1.9-11.5) of disease progression than cluster 1 in multivariable-adjusted, time-to-event analyses. Proteins in cluster 2 mapped to 10 pathways, four of the top five of which were complement or complement-related. A high complement score, constructed from urine complement protein abundance, was strongly correlated to 4 of 5 histopathologic DN features and was associated with a 2.4-fold greater hazard (95% CI, 1.0-5.4) of disease progression than a low complement score. Targeted mass spectrometry of the CRIC-T2D participants, who had an eGFR of 42 mL/min/1.73 m 2 (IQR, 37-49) and 24-hr urine protein of 0.48 g (IQR, 0.10-1.87), showed that the complement score similarly segregated them into rapid and slow DKD progression groups. In both cohorts, the complement score had a linear association with disease progression. Urinary proteomic profiling confirms the association between the complement pathway and rapid DKD progression in two independent cohorts. These results suggest a need to further investigate complement pathway inhibition as a novel treatment for DKD.

Elucidating the Mechanism of Jisheng Shenqi Pills in the Treatment of Diabetic Kidney Disease: Network Pharmacology Combined with Experimental Verification.

While the annual incidence of diabetic kidney disease (DKD) has been soaring, the exact mechanisms underlying its onset and progression remain partially understood. The present study delved into the underlying mechanisms of Jisheng Shenqi Pill (JSP) in the treatment of DKD. The active constituents and prospective targets of JSP were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), while DKD-associated disease targets were obtained from the GeneCards database. Subsequently, Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to assess the overlapping segment of drugs and disease targets. Meanwhile, a component-target-pathway network was constructed to identify pivotal components, targets, and pathways. Molecular docking and molecular dynamics simulation were also carried out to validate the binding efficacy of the pivotal components with the targets. Finally, animal experiments were conducted to corroborate the efficacy of the aforementioned targets and pathways. According to bioinformatics analysis, the primary targets included JUN, TNF, and BAX, while the pivotal pathways involved were AGE/RAGE and PI3K/AKT signaling cascades. In vivo experiments demonstrated that JSP effectively mitigated renal impairment in DKD by reducing renal inflammation and apoptosis. This effect was presumably achieved by modulating the AGERAGE axis and the PI3K/AKT signaling pathway. Our findings imply that JSP could ameliorate renal inflammation and apoptosis in DKD mice by modulating the AGE/RAGE axis and the PI3K/AKT signaling pathway. These findings provide valuable insights into traditional Chinese medicine-based treatments for DKD.