GSK3ß: A ray of hope for the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD), a major microvascular complication of diabetes, is characterized by its complex pathogenesis, high risk of chronic renal failure, and lack of effective diagnosis and treatment methods. GSK3ß (glycogen synthase kinase 3ß), a highly conserved threonine/serine kinase, was found to activate glycogen synthase. As a key molecule of the glucose metabolism pathway, GSK3ß participates in a variety of cellular activities and plays a pivotal role in multiple diseases. However, these effects are not only mediated by affecting glucose metabolism. This review elaborates on the role of GSK3ß in DKD and its damage mechanism in different intrinsic renal cells. GSK3ß is also a biomarker indicating the progression of DKD. Finally, the protective effects of GSK3ß inhibitors on DKD are also discussed.

c-Cbl induced podocin ubiquitination contributes to the podocytes injury in diabetic nephropathy.

The ubiquitination function in diabetic nephropathy (DN) has attracted much attention, but there is a lack of information on its ubiquitylome profile. To examine the differences in protein content and ubiquitination in the kidney between db/db mice and db/m mice, we deployed liquid chromatography-mass spectrometry (LC-MS/MS) to conduct analysis. We determined 145 sites in 86 upregulated modified proteins and 66 sites in 49 downregulated modified proteins at the ubiquitinated level. Moreover, 347 sites among the 319 modified proteins were present only in the db/db mouse kidneys, while 213 sites among the 199 modified proteins were present only in the db/m mouse kidneys. The subcellular localization study indicated that the cytoplasm had the highest proportion of ubiquitinated proteins (31.87%), followed by the nucleus (30.24%) and the plasma membrane (20.33%). The enrichment analysis revealed that the ubiquitinated proteins are mostly linked to tight junctions, oxidative phosphorylation, and thermogenesis. Podocin, as a typical protein of slit diaphragm, whose loss is a crucial cause of proteinuria in DN. Consistent with the results of ubiquitination omics, the K261R mutant of podocin induced the weakest ubiquitination compared with the K301R and K370R mutants. As an E3 ligase, c-Cbl binds to podocin, and the regulation of c-Cbl can impact the ubiquitination of podocin. In conclusion, in DN, podocin ubiquitination contributes to podocyte injury, and K261R is the most significant site. c-Cbl participates in podocin ubiquitination and may be a direct target for preserving the integrity of the slit diaphragm structure, hence reducing proteinuria in DN.

ACSF2 and lysine lactylation contribute to renal tubule injury in diabetes.

AIMS: Lactate accumulation is reported to be a biomarker for diabetic nephropathy progression. Lactate drives lysine lactylation, a newly discovered post-translational modification that is involved in the pathogenesis of cancers and metabolic and inflammatory disease. Here, we aimed to determine whether lysine lactylation is involved in the pathogenesis of diabetic nephropathy. METHODS: Renal biopsy samples from individuals with diabetic nephropathy (n=22) and control samples from individuals without diabetes and kidney disease (n=9) were obtained from the First Affiliated Hospital of Zhengzhou University for immunohistochemical staining. In addition, we carried out global lactylome profiling of kidney tissues from db/m and db/db mice using LC-MS/MS. Furthermore, we assessed the role of lysine lactylation and acyl-CoA synthetase family member 2 (ACSF2) in mitochondrial function in human proximal tubular epithelial cells (HK-2). RESULTS: The expression level of lysine lactylation was significantly increased in the kidneys of individuals with diabetes as well as in kidneys from db/db mice. Integrative lactylome analysis of the kidneys of db/db and db/m mice identified 165 upregulated proteins and 17 downregulated proteins, with an increase in 356 lysine lactylation sites and a decrease in 22 lysine lactylation sites decreased. Subcellular localisation analysis revealed that most lactylated proteins were found in the mitochondria (115 proteins, 269 sites). We further found that lactylation of the K182 site in ACSF2 contributes to mitochondrial dysfunction. Finally, the expression of ACSF2 was notably increased in the kidneys of db/db mice and individuals with diabetic nephropathy. CONCLUSIONS: Our study strongly suggests that lysine lactylation and ACSF2 are mediators of mitochondrial dysfunction and may contribute to the progression of diabetic nephropathy. DATA AVAILABILITY: The LC-MS/MS proteomics data have been deposited in the ProteomeXchange Consortium database ( https://proteomecentral.proteomexchange.org ) via the iProX partner repository with the dataset identifier PXD050070.

Impaired distal renal potassium handling in streptozotocin-induced diabetic mice.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC.NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Role of ferroptosis in chronic kidney disease.

Chronic kidney disease (CKD) has historically been a significant global health concern, profoundly impacting both life and well-being. In the process of CKD, with the gradual loss of renal function, the incidence of various life-threatening complications, such as cardiovascular diseases, cerebrovascular accident, infection and stroke, is also increasing rapidly. Unfortunately, existing treatments exhibit limited ability to halt the progression of kidney injury in CKD, emphasizing the urgent need to delve into the precise molecular mechanisms governing the occurrence and development of CKD while identifying novel therapeutic targets. Renal fibrosis, a typical pathological feature of CKD, plays a pivotal role in disrupting normal renal structures and the loss of renal function. Ferroptosis is a recently discovered iron-dependent form of cell death characterized by lipid peroxide accumulation. Ferroptosis has emerged as a potential key player in various diseases and the initiation of organ fibrosis. Substantial evidence suggests that ferroptosis may significantly contribute to the intricate interplay between CKD and its progression. This review comprehensively outlines the intricate relationship between CKD and ferroptosis in terms of iron metabolism and lipid peroxidation, and discusses the current landscape of pharmacological research on ferroptosis, shedding light on promising avenues for intervention. It further illustrates recent breakthroughs in ferroptosis-related regulatory mechanisms implicated in the progression of CKD, thereby providing new insights for CKD treatment. Video Abstract.

Novel immune cross-talk between inflammatory bowel disease and IgA nephropathy.

The mechanisms underlying the complex correlation between immunoglobulin A nephropathy (IgAN) and inflammatory bowel disease (IBD) remain unclear. This study aimed to identify the optimal cross-talk genes, potential pathways, and mutual immune-infiltrating microenvironments between IBD and IgAN to elucidate the linkage between patients with IBD and IgAN. The IgAN and IBD datasets were obtained from the Gene Expression Omnibus (GEO). Three algorithms, CIBERSORTx, ssGSEA, and xCell, were used to evaluate the similarities in the infiltrating microenvironment between the two diseases. Weighted gene co-expression network analysis (WGCNA) was implemented in the IBD dataset to identify the major immune infiltration modules, and the Boruta algorithm, RFE algorithm, and LASSO regression were applied to filter the cross-talk genes. Next, multiple machine learning models were applied to confirm the optimal cross-talk genes. Finally, the relevant findings were validated using histology and immunohistochemistry analysis of IBD mice. Immune infiltration analysis showed no significant differences between IBD and IgAN samples in most immune cells. The three algorithms identified 10 diagnostic genes, MAPK3, NFKB1, FDX1, EPHX2, SYNPO, KDF1, METTL7A, RIDA, HSDL2, and RIPK2; FDX1 and NFKB1 were enhanced in the kidney of IBD mice. Kyoto Encyclopedia of Genes and Genomes analysis showed 15 mutual pathways between the two diseases, with lipid metabolism playing a vital role in the cross-talk. Our findings offer insights into the shared immune mechanisms of IgAN and IBD. These common pathways, diagnostic cross-talk genes, and cell-mediated abnormal immunity may inform further experimental studies.

Inhibition of the glycogen synthase kinase 3ß-hypoxia-inducible factor 1α pathway alleviates NLRP3-mediated pyroptosis induced by high glucose in renal tubular epithelial cells.

NEW FINDINGS: What is the central question of this study? Activation of the glycogen synthase kinase 3 ß (GSK-3ß)-hypoxia-inducible factor 1 α (HIF-1α) pathway results in stimulation of pyroptosis under high glucose, and exerts actions in a number renal diseases: does this pathway have a role in renal tubular epithelial cells? What is the main finding and its importance? Down-regulation of GSK-3ß can inhibit pyroptosis of renal tubular epithelial cells induced by high glucose and this may be related to down-regulation of HIF-1α. This role of the GSK-3ß-HIF-1α pathway has not previously been reported and identifies a potential new therapeutic target in diabetic nephropathy. ABSTRACT: Diabetic nephropathy (DN) is not only one of the main complications of diabetes, but also has a high incidence rate and a high mortality rate. Glycogen synthase kinase 3 ß (GSK-3ß) and hypoxia-inducible factor 1 α (HIF-1α) have been demonstrated to influence DN by regulating pyroptosis. This study aimed to investigate the effect of the GSK-3ß-HIF-1α pathway on pyroptosis of high-glucose (HG)-induced renal tubular cells. Mouse renal proximal tubular epithelial cells (TKPT cells) were induced by HG to simulate DN cell and we transfected TKPT cells with GSK-3ß knockdown lentivirus. Western blot analysis confirmed the transfection effects and detected the expression of GSK-3ß, HIF-1α, Nod-like receptor protein 3 (NLRP3), cleaved-caspase-1, pro-caspase-1, gasdermin D (GSDMD) and GSDMD-N. The expression of GSDMD-N and HIF-1α were also verified by immunofluorescence. The levels of interleukin (IL)-1ß and IL-18 were measured by enzyme linked immunosorbent assay. Flow cytometric analysis determined the apoptosis rate. Results showed that HIF-1α expression was increased in HG-induced TKPT cells, and GSK-3ß knockdown could decrease the levels of NLRP3, cleaved-caspase-1, GSDMD-N and HIF-1α, verified by immunofluorescence. Moreover, GSK-3ß knockdown suppressed the expression of IL-1ß and IL-18, and reduced the apoptosis rate. Lithium chloride (LiCl) interference could cause the same changes as GSK-3ß knockdown for HG-induced TKPT cells, and dimethyloxallyl glycine could reverse the effect of GSK-3ß-knockdown interference. Our studies definitively demonstrate that the GSK-3ß-HIF-1α signalling pathway mediates HG-stimulated pyroptosis in renal tubular epithelial cells and that down-regulation of GSK-3ß inhibited HG-induced pyroptosis by inhibiting the expression of HIF-1α. These findings suggest a new potential target for the treatment of DN.

MiR-138 plays an important role in diabetic nephropathy through SIRT1-p38-TTP regulatory axis.

Diabetic nephropathy (DN) is the main cause of chronic kidney disease (CKD) and is one of the most common and serious complications of diabetes mellitus (DM). Sirtuin 1 (SIRT1) and tristetraprolin (TTP) are two important protective factors in DN; however, the regulatory relationship between SIRT1 and TTP, and the underneath mechanism are interesting but still unclear. Identifying the key factors that regulate SIRT1 or TTP may be of great value to the understanding and treatment of the DN. In this study, through systematic experimental methods, we found that the expression of miR-138 was significantly upregulated in DN clinical patient samples, and our experimental results suggested that miR-138 could bind the 3'-UTR of SIRT1 and inhibit its expression in both cultured podocytes and db/db mice kidney tissues. Furthermore, our in vitro and in vivo experiments also indicated miR-138 could target SIRT1 and affect TTP through p38 pathway. And downregulation of miR-138 attenuated podocyte injury and showed some extent of therapeutic effects in DN mice models. Our findings revealed that the regulatory axis of miR-138-SIRT1-p38-TTP might play a key role in DN. We believe that these findings may be of some value for deepening the understanding of DN and may serve as a reference for future treatment of this disease.

Prevalence and risk factors of chronic kidney disease and diabetic kidney disease in a central Chinese urban population: a cross-sectional survey.

BACKGROUND: This study was conducted to evaluate and update the current prevalence of and risk factors for chronic kidney disease (CKD) and diabetic kidney disease (DKD) in a central Chinese urban population. METHODS: From December 2017 to June 2018, a total of 5231 subjects were randomly enrolled from 3 communities in 3 districts of Zhengzhou. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min.1.73m2 or urinary albumin to creatinine ratio ≥ 30 mg/g (albuminuria). Diabetic subjects with systolic blood pressure > 140 mmHg, albuminuria or an eGFR less than 60 mL/min/1.73 m2 were classified as having DKD. Participants completed a questionnaire assessing lifestyle and relevant medical history, and blood and urine specimens were taken. Serum creatinine, uric acid, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein and urinary albumin were assessed. The age- and sex-adjusted prevalences of CKD and DKD were calculated, and risk factors associated with the presence of reduced eGFR, albuminuria, DKD, severity of albuminuria and progression of reduced renal function were analyzed by binary and ordinal logistic regression. RESULTS: The overall adjusted prevalence of CKD was 16.8% (15.8-17.8%) and that of DKD was 3.5% (3.0-4.0%). Decreased renal function was detected in 132 participants (2.9, 95% confidence interval [CI]: 2.5-3.2%), whereas albuminuria was found in 858 participants (14.9, 95% CI: 13.9-15.9%). In all participants with diabetes, the prevalence of reduced eGFR was 6.3% (95% CI = 3.9-8.6%) and that of albuminuria was 45.3% (95% CI = 40.4-50.1%). The overall prevalence of CKD in participants with diabetes was 48.0% (95% CI = 43.1-52.9%). The results of the binary and ordinal logistic regression indicated that the factors independently associated with a higher risk of reduced eGFR and albuminuria were older age, sex, smoking, alcohol consumption, overweight, obesity, diabetes, hypertension, dyslipidemia and hyperuricemia. CONCLUSIONS: Our study shows the current prevalence of CKD and DKD in residents of Central China. The high prevalence suggests an urgent need to implement interventions to relieve the high burden of CKD and DKD in China.

Ferroptosis: a potential bridge linking gut microbiota and chronic kidney disease.

Ferroptosis is a novel form of lipid peroxidation-driven, iron-dependent programmed cell death. Various metabolic pathways, including those involved in lipid and iron metabolism, contribute to ferroptosis regulation. The gut microbiota not only supplies nutrients and energy to the host, but also plays a crucial role in immune modulation and metabolic balance. In this review, we explore the metabolic pathways associated with ferroptosis and the impact of the gut microbiota on host metabolism. We subsequently summarize recent studies on the influence and regulation of ferroptosis by the gut microbiota and discuss potential mechanisms through which the gut microbiota affects ferroptosis. Additionally, we conduct a bibliometric analysis of the relationship between the gut microbiota and ferroptosis in the context of chronic kidney disease. This analysis can provide new insights into the current research status and future of ferroptosis and the gut microbiota.

The intervention of cannabinoid receptor in chronic and acute kidney disease animal models: a systematic review and meta-analysis.

AIM: Cannabinoid receptors are components of the endocannabinoid system that affect various physiological functions. We aim to investigate the effect of cannabinoid receptor modulation on kidney disease. METHODS: PubMed, Web of Science databases, and EMBASE were searched. Articles selection, data extraction and quality assessment were independently performed by two investigators. The SYRCLE's RoB tool was used to assess the risk of study bias, and pooled SMD using a random-effect model and 95% CIs were calculated. Subgroup analyses were conducted in preselected subgroups, and publication bias was evaluated. We compared the effects of CB1 and CB2 antagonists and/or knockout and agonists and/or genetic regulation on renal function, blood glucose levels, body weight, and pathological damage-related indicators in different models of chronic and acute kidney injury. RESULTS: The blockade or knockout of CB1 could significantly reduce blood urea nitrogen [SMD,- 1.67 (95% CI - 2.27 to - 1.07)], serum creatinine [SMD, - 1.88 (95% CI - 2.91 to - 0.85)], and albuminuria [SMD, - 1.60 (95% CI - 2.16 to - 1.04)] in renal dysfunction animals compared with the control group. The activation of CB2 group could significantly reduce serum creatinine [SMD, - 0.97 (95% CI - 1.83 to - 0.11)] and albuminuria [SMD, - 2.43 (95% CI - 4.63 to - 0.23)] in renal dysfunction animals compared with the control group. CONCLUSIONS: The results suggest that targeting cannabinoid receptors, particularly CB1 antagonists and CB2 agonists, can improve kidney function and reduce inflammatory responses, exerting a renal protective effect and maintaining therapeutic potential in various types of kidney disease.

Mitochondria-associated endoplasmic reticulum membrane (MAM): a dark horse for diabetic cardiomyopathy treatment.

Diabetic cardiomyopathy (DCM), an important complication of diabetes mellitus (DM), is one of the most serious chronic heart diseases and has become a major cause of heart failure worldwide. At present, the pathogenesis of DCM is unclear, and there is still a lack of effective therapeutics. Previous studies have shown that the homeostasis of mitochondria and the endoplasmic reticulum (ER) play a core role in maintaining cardiovascular function, and structural and functional abnormalities in these organelles seriously impact the occurrence and development of various cardiovascular diseases, including DCM. The interplay between mitochondria and the ER is mediated by the mitochondria-associated ER membrane (MAM), which participates in regulating energy metabolism, calcium homeostasis, mitochondrial dynamics, autophagy, ER stress, inflammation, and other cellular processes. Recent studies have proven that MAM is closely related to the initiation and progression of DCM. In this study, we aim to summarize the recent research progress on MAM, elaborate on the key role of MAM in DCM, and discuss the potential of MAM as an important therapeutic target for DCM, thereby providing a theoretical reference for basic and clinical studies of DCM treatment.

Perspectives on the involvement of the gut microbiota in salt-sensitive hypertension.

Salt-sensitivity hypertension (SSH) is an independent predictor of cardiovascular event-related death. Despite the extensiveness of research on hypertension, which covers areas such as the sympathetic nervous system, the renin-angiotensin system, the vascular system, and the immune system, its pathogenesis remains elusive, with sub-optimal blood pressure control in patients. The gut microbiota is an important component of nutritional support and constitutes a barrier in the host. Long-term high salt intake can lead to gut microbiota dysbiosis and cause significant changes in the expression of gut microbiota-related metabolites. Of these metabolites, short chain fatty acids (SCFAs), trimethylamine oxide, amino acids, bile acids, and lipopolysaccharide are essential mediators of microbe-host crosstalk. These metabolites may contribute to the incidence and development of SSH via inflammatory, immune, vascular, and nervous pathways, among others. In addition, recent studies, including those on the histone deacetylase inhibitory mechanism of SCFAs and the blood pressure-decreasing effects of H2S via vascular activation, suggest that several proteins and factors in the classical pathway elicit their effects through multiple non-classical pathways. This review summarizes changes in the gut microbiota and its related metabolites in high-salt environments, as well as corresponding treatment methods for SSH, such as diet management, probiotic and prebiotic use, antibiotic use, and fecal transplantation, to provide new insights and perspectives for understanding SSH pathogenesis and the development of strategies for its treatment.

Emerging role of antidiabetic drugs in cardiorenal protection.

The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

VDR Activation Attenuates Renal Tubular Epithelial Cell Ferroptosis by Regulating Nrf2/HO-1 Signaling Pathway in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.

Defective natriuresis contributes to hyperkalemia in db/db mice during potassium supplementation.

OBJECTIVES: Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K+-induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS: In this study, we examined the impact of high-K+ intake on renal Na+/K+ transport by determining the expression of major apical Na+ transporters, diuretics responses (as a proxy for specific Na+ transporter function), urinary Na+/K+ excretion, and plasma Na+/K+ concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS: Although db/m mice exhibited increased fractional excretion of sodium (FENa) and fractional excretion of potassium (FEK) under high-K+ intake, these responses were largely blunted in db/db mice, suggesting impaired K+-induced natriuresis and kaliuresis in diabetes. Consequently, high-K+ intake increased plasma K+ levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na+ channel (ENaC), as high-K+ intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K+ diet, indicating a key role for NCC in K+-loaded diabetic mice. Treatment with metformin enhanced urinary Na+/K+ excretion and normalized plasma K+ levels in db/db mice with a high-K+ diet, at least partially, by suppressing NCC activity. CONCLUSION: Collectively, the impaired K+-induced natriuresis in diabetic mice under high-K+ intake may be primarily attributed to impaired NCC-mediated renal K+ excretion, despite the role of NHE3.

The Road from AKI to CKD: Molecular Mechanisms and Therapeutic Targets of Ferroptosis.

Acute kidney injury (AKI) is a prevalent pathological condition that is characterized by a precipitous decline in renal function. In recent years, a growing body of studies have demonstrated that renal maladaptation following AKI results in chronic kidney disease (CKD). Therefore, targeting the transition of AKI to CKD displays excellent therapeutic potential. However, the mechanism of AKI to CKD is mediated by multifactor, and there is still a lack of effective treatments. Ferroptosis, a novel nonapoptotic form of cell death, is believed to have a role in the AKI to CKD progression. In this study, we retrospectively examined the history and characteristics of ferroptosis, summarized ferroptosis's research progress in AKI and CKD, and discussed how ferroptosis participates in regulating the pathological mechanism in the progression of AKI to CKD. Furthermore, we highlighted the limitations of present research and projected the future evolution of ferroptosis. We hope this work will provide clues for further studies of ferroptosis in AKI to CKD and contribute to the study of effective therapeutic targets to prevent the progression of kidney diseases.

Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions.

Diabetic cardiomyopathy (DCM) mainly refers to myocardial metabolic dysfunction caused by high glucose, and hyperglycemia is an independent risk factor for cardiac function in the absence of coronary atherosclerosis and hypertension. DCM, which is a severe complication of diabetes, has become the leading cause of heart failure in diabetic patients. The initial symptoms are inconspicuous, and patients gradually exhibit left ventricular dysfunction and eventually develop total heart failure, which brings a great challenge to the early diagnosis of DCM. To date, the underlying pathological mechanisms of DCM are complicated and have not been fully elucidated. Although there are therapeutic strategies available for DCM, the treatment is mainly focused on controlling blood glucose and blood lipids, and there is a lack of effective drugs targeting myocardial injury. Thus, a large percentage of patients with DCM inevitably develop heart failure. Given the neglected initial symptoms, the intricate cellular and molecular mechanisms, and the lack of available drugs, it is necessary to explore early diagnostic biomarkers, further understand the signaling pathways involved in the pathogenesis of DCM, summarize the current therapeutic strategies, and develop new targeted interventions.

Broadening horizons: the multifaceted functions of ferroptosis in kidney diseases.

Ferroptosis is an iron-dependent programmed cell death pattern that is characterized by iron overload, reactive oxygen species (ROS) accumulation and lipid peroxidation. Growing viewpoints support that the imbalance of iron homeostasis and the disturbance of lipid metabolism contribute to tissue or organ injury in various kidney diseases by triggering ferroptosis. At present, the key regulators and complicated network mechanisms associated with ferroptosis have been deeply studied; however, its role in the initiation and progression of kidney diseases has not been fully revealed. Herein, we aim to discuss the features, key regulators and complicated network mechanisms associated with ferroptosis, explore the emerging roles of organelles in ferroptosis, gather its pharmacological progress, and systematically summarize the most recent discoveries about the crosstalk between ferroptosis and kidney diseases, including renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), autosomal dominant polycystic kidney disease (ADPKD), renal fibrosis, lupus nephritis (LN) and IgA nephropathy. We further conclude the potential therapeutic strategies by targeting ferroptosis for the prevention and treatment of kidney diseases and hope that this work will provide insight for the further study of ferroptosis in the pathogenesis of kidney-related diseases.

Corrigendum: Relationship between serum iPTH and peritonitis episodes in patients undergoing continuous ambulatory peritoneal dialysis.

[This corrects the article DOI: 10.3389/fendo.2023.1081543.].