Cadmium (Cd), a well-known toxic heavy metal, adversely affects multiple organs. The SGLT-2 inhibitor empagliflozin (EMPA) exhibits significant antioxidant properties and hypoglycemic potential. This study aimed to investigate the hepatoprotective effect of EMPA against Cd-induced liver injury and elucidate its molecular mechanisms. Thirty-two male rats were allocated into four groups of eight rats each: group I (control group), group II (EMPA group), group III (Cd group), and group IV (Cd + EMPA group). Cd intake disrupted liver enzymes (ALT, AST, and ALP) and impaired hepatic histological architecture. Cd induced hepatic oxidative stress, as evidenced by increased MDA levels and reduced antioxidant enzymes, including SOD, GPx, and CAT. It downregulated the Nrf2/HO-1 pathway and elevated proinflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, Cd increased ER stress markers GRP78 and CHOP, along with apoptotic markers Bax and caspase-3 while decreasing anti-apoptotic Bcl-2 and reducing the autophagic indicator Beclin-1. Interestingly, EMPA administration in the Cd + EMPA group attenuated Cd-induced hepatic deterioration, improving hepatocyte structure. This beneficial effect was driven by the downregulation of hepatic oxidative stress, inflammation, ER stress, and apoptosis, alongside the upregulation of the autophagy process. In conclusion, this study highlights the hepatoprotective effect of EMPA against Cd-induced liver injury, elucidating its underlying molecular mechanisms.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) offer significant cardiovascular and kidney protection, independent of diabetes mellitus (DM). Recent cohort studies also suggest that SGLT2i can decrease the risk of nephrolithiasis in patients with DM. We aimed to use both animal models and human data to investigate whether SGLT2i can prevent nephrolithiasis and explored autophagy as a possible mechanism.

We utilised SGLT2i, dapagliflozin (DAPA), on a glyoxylate (GOX)-induced calcium oxalate (CaOx) nephrolithiasis non-DM mouse model to test whether SGLT2i inhibited CaOx stone formation through modulating autophagy. Moreover, the clinical data retrieved from the National Health Insurance Research Database was analysed to confirm the findings from animal models.

DAPA increased urine citrate, magnesium, pH, and decreased oxalate, effectively inhibiting CaOx stones in GOX mice. While autophagy was increased in the kidneys of GOX mice, as demonstrated by upregulated AMP-activated protein kinase (AMPK) and increased LC3B conversion; impaired autophagic flux was indicated by p62 accumulation. DAPA improved autophagy by downregulating mammalian target of rapamycin (mTOR), AMPK, and restoring autophagic flux. Rapamycin co-treatment preserved DAPA's nephrolithiasis inhibition, while hydroxychloroquine (HCQ) co-treatment abolished it. Finally, cohort data confirmed that SGLT2i reduced nephrolithiasis risk, but this protective effect disappeared if HCQ had been used within the prior year, suggesting that HCQ may compromise SGLT2i's protection against nephrolithiasis.

SGLT2i, DAPA, inhibits nephrolithiasis by restoring impaired autophagic flux, and co-administration with autophagy inhibitor, HCQ, compromises SGLT2i's protection.

This research was funded by grants from the National Science and Technology Council, Taiwan (110-2314-B-006-023, 110-2320-B-006-017MY3, and 112-2314-B-006-058) and the research grants (NCKUH-11202005, -11210020) from the National Cheng Kung University Hospital, Tainan, Taiwan.

Renal risk variants in the apolipoprotein L1 (APOL1) gene confer protection against trypanosomiasis, but these risk variants (G1 and G2 variants) also predispose to kidney disease among individuals, especially from Sub-SaharanAfrica. Currently, the mechanisms of how these renal risk variants induce kidney damage are not precisely defined, but lysosomal and mitochondrial dysfunction, altered ion channel activity, altered autophagy, and disordered immunity are suggested. Currently, there is no specific treatment for APOL1 kidney disease (APOL1-KD) although several potential disease-specific therapeutic agents are being evaluated in clinical trials. Non-specific interventions include proteinuria screening, salt restriction, and renin-angiotensin-aldosterone system inhibition but are not sufficient to prevent kidney disease progression in APOL1-KD. Given the lack of specific treatment options, more efforts are necessary to reduce kidney disease progression. Sodium glucose co-transport-2 (SGLT2) inhibitors (SGLT2i) are gaining attention for benefits in proteinuric kidney diseases and exert many beneficial effects which theoretically may be beneficial in the context of APOL1-KD. These beneficial effects include but are not limited to increased natriuresis, decreased proteinuria/albuminuria, and mitochondrial dysfunction. SGLT2i have antioxidant, anti-inflammatory and anti-fibrotic effects. In the current review, we highlight the potential reasons for exploring the use of SGLT2i in APOL1-KD. Future studies are warranted to explore if SGLT2i use can provide protection in APOL1-KD.

As a microvascular complication, diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease worldwide. While the underlying pathophysiology driving transition of diabetic kidney disease to renal failure is yet to be fully understood, recent studies suggest that cellular senescence is central in disease development and progression. Consequently, understanding the molecular mechanisms which initiate and drive senescence in response to the diabetic milieu is crucial in developing targeted therapies that halt progression of renal disease.

To understand the mechanistic pathways underpinning cellular senescence in the context of diabetic kidney disease, we reviewed the literature using PubMed for English language articles that contained key words related to senescence, inflammation, fibrosis, senescence-associated secretory phenotype (SASP), autophagy, and diabetes.

Aberrant accumulation of metabolically active senescent cells is a notable event in the progression of diabetic kidney disease. Through autocrine- and paracrine-mediated mechanisms, resident senescent cells potentiate inflammation and fibrosis through increased expression and secretion of pro-inflammatory cytokines, chemoattractants, recruitment of immune cells, myofibroblast activation, and extracellular matrix remodelling. Compounds that eliminate senescent cells and/or target the SASP - including senolytic and senomorphics drugs - demonstrate promising results in reducing the senescent cell burden and associated pro-inflammatory effect.

Here we evidence the link between senescence and diabetic kidney disease and highlight underlying molecular mechanisms and potential therapeutic targets that could be exploited to delay disease progression and improve outcomes for individuals with the disease. Trials are now required to translate their therapeutic potential to a clinical setting.

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.

The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.

The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes increasingly evident that guideline-directed medical therapy cannot be one-size-fits-all across a wide range of ejection fractions (EFs) and various aetiologies. Therefore, classifications solely relying on EF and natriuretic peptide make optimization of treatment challenging, and there is a growing exploration of new indicators that enable efficient risk stratification of HF patients. Particularly when considering HF as a multi-organ interaction syndrome, the cardiorenal interaction plays a central role in its pathophysiology, and albuminuria has gained great prominence as its biomarker, independent from glomerular filtration rate. Albuminuria has been shown to exhibit a linear correlation with cardiovascular disease and HF prognosis in multiple epidemiological studies, ranging from normal (<30 mg/g) to high levels (>300 mg/g). However, on the other hand, it is only recently that the details of the pathological mechanisms that give rise to albuminuria have begun to be elucidated, including the efficient compaction/tightening of the glomerular basement membrane by podocytes and mesangial cells. Interestingly, renal disease, diabetes, and HF damage these components associated with albuminuria, and experimental models have demonstrated that recently developed HF drugs reduce albuminuria by ameliorating these pathological phenotypes. In this review, facing the rapid expansion of horizons in HF treatment, we aim to clarify the current understanding of the pathophysiology of albuminuria and explore the comprehensive understanding of albuminuria by examining the clinically established evidence to date, the pathophysiological mechanisms leading to its occurrence, and the outcomes of clinical studies utilizing various drug classes committed to specific pathological mechanisms to put albuminuria as a novel axis to depict the pathophysiology of HF.

Diabetic nephropathy (DN) is a globally widespread complication of diabetes mellitus (DM). Research indicates that pioglitazone and linagliptin mitigate the risk of DN by reducing inflammation, oxidative stress, and fibrosis. The role of tamsulosin in DN is less studied, but it may contribute to reducing oxidative stress and inflammatory responses. The protective effects of combining pioglitazone, linagliptin, and tamsulosin on the kidneys have scarcely been investigated. This study examines the individual and combined effects of these drugs on DN in Wistar rats. Diabetic rats were treated with tamsulosin, pioglitazone, and linagliptin for six weeks. We assessed food and water intake, estimated glomerular filtration rate (eGFR), histological markers, urea, creatinine, glucose, NF-κB, IL-1, IL-10, TGF-β, and Col-IV using immunofluorescence and qPCR. The DN group exhibited hyperglycaemia, reduced eGFR, and tissue damage. Tamsulosin and linagliptin improved eGFR, decreased urinary glucose, and repaired tissue damage. Pioglitazone and its combinations restored serum and urinary markers and reduced tissue damage. Linagliptin lowered serum creatinine and tissue injury. In conclusion, tamsulosin, linagliptin, and pioglitazone demonstrated renoprotective effects in DN.

The lysosomal autophagic pathway plays a fundamental role in cellular and tissue homeostasis, and its deregulation is linked to human pathologies including kidney diseases. Autophagy can randomly degrade cytoplasmic components in a nonselective manner commonly referred to as bulk autophagy. In contrast, selective forms of autophagy specifically target cytoplasmic structures such as organelles and protein aggregates, thereby being important for cellular quality control and organelle homeostasis.

Research during the past decades has begun to elucidate the role of selective autophagy in kidney physiology and kidney diseases.

In this review, we will summarize the knowledge on lipophagy and mitophagy, two forms of selective autophagy important in renal epithelium homeostasis, and discuss how their deregulations contribute to renal disease progression.

Cell deaths maintain the normal function of tissues and organs. In pathological conditions, the abnormal activation or disruption of cell death often leads to pathophysiological effects. Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is linked to high mortality and morbidity rates, imposing a substantial burden on global healthcare systems and economies. Loss and detachment of podocytes are key pathological changes in the progression of DKD. This review explores the potential mechanisms of apoptosis, necrosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and podoptosis in podocytes, focusing on how different cell death modes contribute to the progression of DKD. It recognizes the limitations of current research and presents the latest basic and clinical research studies targeting podocyte death pathways in DKD. Lastly, it focuses on the future of targeting podocyte cell death to treat DKD, with the intention of inspiring further research and the development of therapeutic strategies.

The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence.

Diabetic kidney disease (DKD) is the primary cause of chronic kidney and end-stage renal disease. Glomerular podocyte loss and death are pathological hallmarks of DKD, and programmed cell death (PCD) in podocytes is crucial in DKD progression. PCD involves apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis. During DKD, PCD in podocytes is severely impacted and primarily characterized by accelerated podocyte apoptosis and suppressed autophagy. These changes lead to a gradual decrease in podocyte numbers, impairing the glomerular filtration barrier function and accelerating DKD progression. However, research on the interactions between the different types of PCD in podocytes is lacking. This review focuses on the novel roles and mechanisms of PCD in the podocytes of patients with DKD. Additionally, we summarize clinical drugs capable of regulating podocyte PCD, present challenges and prospects faced in developing drugs related to podocyte PCD and suggest that future research should further explore the detailed mechanisms of podocyte PCD and interactions among different types of PCD.

The discovery of inhibitors for sodium-glucose cotransporter 2 (SGLT2) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) has significantly improved type 2 diabetes management. Large-scale clinical studies have shown that both SGLT2 inhibitors and GLP-1 RA enhance cardiovascular health. Benefits include reduced cardiovascular disease risk, lower mortality, fewer heart failure hospitalizations (SGLT2 inhibitors), and stroke prevention (GLP-1 RA). Additionally, these drugs slow chronic kidney disease progression. This comprehensive treatment targets vascular events. Despite differences, both drug classes are crucial. GLP-1 RA mainly reduce stroke risk, while SGLT2 inhibitors alleviate heart failure. Our findings, based on a literature review, will address the renal and cardiac effects of SGLT2 inhibitors and GLP-1 RA in both diabetics and non-diabetics, highlighting their combined benefits for heart conditions.

Chronic kidney disease (CKD) is a noncommunicable condition that has become a major healthcare burden across the globe, often underdiagnosed and associated with low awareness. The main cause that leads to the development of renal impairment is diabetes mellitus and, in contrast to other chronic complications such as retinopathy or neuropathy, it has been suggested that intensive glycemic control is not sufficient in preventing the development of diabetic kidney disease. Nevertheless, a novel class of antidiabetic agents, the sodium-glucose cotransporter-2 inhibitors (SGLT2i), have shown multiple renoprotective properties that range from metabolic and hemodynamic to direct renal effects, with a major impact on reducing the risk of occurrence and progression of CKD. Thus, this review aims to summarize current knowledge regarding the renoprotective mechanisms of SGLT2i and to offer a new perspective on this innovative class of antihyperglycemic drugs with proven pleiotropic beneficial effects that, after decades of no significant progress in the prevention and in delaying the decline of renal function, start a new era in the management of patients with CKD.

Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have evolved from their initial role as antidiabetic drugs to garner recognition for their remarkable cardio-protective and reno-protective attributes. They have become a crucial component of therapeutic guidelines for congestive heart failure and proteinuric chronic kidney disease (CKD). These benefits extend beyond glycemic control, because improvements in cardiovascular and renal outcomes occur swiftly. Recent studies have unveiled the immunomodulatory properties of SGLT2 inhibitors; thus, shedding light on their potential to influence the immune system and inflammation. This comprehensive review explores the current state of knowledge regarding the impact of SGLT2 inhibitors on the immune system and inflammation, focusing on preclinical and clinical evidence. The review delves into their antiinflammatory and immunomodulating effects, offering insights into clinical implications, and exploring emerging research areas related to their prospective immunomodulatory impact.

Elucidating the molecular mechanism of autophagy was a landmark in understanding not only the physiology of cells and tissues, but also the pathogenesis of diverse diseases, including diabetes and metabolic disorders. Autophagy of pancreatic β-cells plays a pivotal role in the maintenance of the mass, structure and function of β-cells, whose dysregulation can lead to abnormal metabolic profiles or diabetes. Modulators of autophagy are being developed to improve metabolic profile and β-cell function through the removal of harmful materials and rejuvenation of organelles, such as mitochondria and endoplasmic reticulum. Among the known antidiabetic drugs, glucagon-like peptide-1 receptor agonists enhance the autophagic activity of β-cells, which might contribute to the profound effects of glucagon-like peptide-1 receptor agonists on systemic metabolism. In this review, the results from studies on the role of autophagy in β-cells and their implication in the development of diabetes are discussed. In addition to non-selective (macro)autophagy, the role and mechanisms of selective autophagy and other minor forms of autophagy that might occur in β-cells are discussed. As β-cell failure is the ultimate cause of diabetes and unresponsiveness to conventional therapy, modulation of β-cell autophagy might represent a future antidiabetic treatment approach, particularly in patients who are not well managed with current antidiabetic therapy.

Tacrolimus (TAC) is a frequently used immunosuppressive medication in organ transplantation. However, its nephrotoxic impact limits its long-term usage. This study aims to investigate the effect of linagliptin (Lina) on TAC-induced renal injury and its underlying mechanisms.

Thirty-two Sprague Dawley rats were treated with TAC (1.5 mg/kg/day, subcutaneously) and/or Lina (5 mg/kg/day, orally) for 4 weeks. Histological examination was conducted, and serum and urinary biomarkers were measured to assess kidney function and integrity. Furthermore, ELISA, Western blot analysis and immunohistochemical assay were employed to determine signaling molecules of oxidative stress, profibrogenic, hypoxic, and apoptotic proteins. Tacrolimus caused renal dysfunction and histological deterioration evidenced by increased serum creatinine, blood urea nitrogen (BUN), urinary cystatin C, and decreased serum albumin as well as elevated tubular injury and interstitial fibrosis scores. Additionally, TAC significantly increased the expression of collagen type-1, alpha-smooth muscle actin (α-SMA), plasminogen activator inhibitor-1 (PAI-1), and transforming growth factor-beta1 (TGF-β1) renal content. Moreover, TAC decreased the expression of nuclear factor erythroid-2-related factor2 (Nrf2), heme oxygenase 1 (HO-1), and mitochondrial superoxide dismutase (SOD2). In addition, TAC increased protein expression of hypoxia-inducible factor1-alpha (HIF-1α), connective tissue growth factor (CTGF), inducible nitric oxide synthase (iNOS), 8-hydroxy-2-deoxyguanosine (8-OHdG), as well as nitric oxide (NO), 4-hydroxynonenal, caspase-3 and Bax renal contents. Furthermore, TAC decreased Bcl-2 renal contents. The Lina administration markedly attenuated these alterations.

Lina ameliorated TAC-induced kidney injury through modulation of oxidative stress, hypoxia, and apoptosis related proteins.

Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease and currently there are no specific and effective drugs for its treatment. Podocyte injury is a detrimental feature and the major cause of albuminuria in DN. We previously reported Tangshen Formula (TSF), a Chinese herbal medicine, has shown therapeutic effects on DN. However, the underlying mechanisms remain obscure.

This study aimed to explore the protective effect of TSF on podocyte apoptosis in DN and elucidate the potential mechanism.

The effects of TSF were assessed in a murine model using male KKAy diabetic mice, as well as in advanced glycation end products-stimulated primary mice podocytes. Transcription factor EB (TFEB) knockdown primary podocytes were employed for mechanistic studies. In vivo and in vitro studies were performed and results assessed using transmission electron microscopy, immunofluorescence staining, and western blotting.

TSF treatment alleviated podocyte apoptosis and structural impairment, decreased albuminuria, and mitigated renal dysfunction in KKAy mice. Notably, TSF extracted twice showed a more significant reduction in proteinuria than TSF extracted three times. Accumulation of autophagic biomarkers p62 and LC3, and aberrant autophagic flux in podocytes of DN mice were significantly altered by TSF therapy. Consistent with the in vivo results, TSF prevented the apoptosis of primary podocytes exposed to AGEs and activated autophagy. However, the anti-apoptosis capacity of TSF was countered by the autophagy-lysosome inhibitor chloroquine. We found that TSF increased the nuclear translocation of TFEB in diabetic podocytes, and thus upregulated transcription of its several autophagic target genes. Pharmacological activation of TFEB by TSF accelerated the conversion of autophagosome to autolysosome and lysosomal biogenesis, further augmented autophagic flux. Conversely, TFEB knockdown negated the favorable effects of TSF on autophagy in AGEs-stimulated primary podocytes.

These findings indicate TSF appears to attenuate podocyte apoptosis and promote autophagy in DN via the TFEB-mediated autophagy-lysosome system. Thus, TSF may be a therapeutic candidate for DN.

An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer's disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25-35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25-35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25-35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25-35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25-35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.

Impaired fatty acid oxidation (FAO) is a metabolic hallmark of renal tubular epithelial cells (RTECs) under diabetic conditions. Disturbed FAO may promote cellular oxidative stress and insufficient energy production, leading to ferroptosis subsequently. Canagliflozin, an effective anti-hyperglycemic drug, may exert potential reno-protective effects by upregulating FAO and inhibiting ferroptosis in RTECs. However, the mechanisms involved remain unclear. The present study is aimed to characterize the detailed mechanisms underlying the impact of canagliflozin on FAO and ferroptosis. Type 2 diabetic db/db mice were administrated daily by gavage with canagliflozin (20 mg/kg/day, 40 mg/kg/day) or positive control drug pioglitazone (10 mg/kg/day) for 12 weeks. The results showed canagliflozin effectively improved renal function and structure, reduced lipid droplet accumulation, enhanced FAO with increased ATP contents and CPT1A expression, a rate-limiting enzyme of FAO, and relieved ferroptosis in diabetic mice. Moreover, overexpression of FOXA1, a transcription factor related with lipid metabolism, was observed to upregulate the level of CPT1A, and further alleviated ferroptosis in high glucose cultured HK-2 cells. Whereas FOXA1 knockdown had the opposite effect. Mechanistically, chromatin immunoprecipitation assay and dual-luciferase reporter gene assay results demonstrated that FOXA1 transcriptionally promoted the expression of CPT1A through a sis-inducible element located in the promoter region of the protein. In conclusion, these data suggest that canagliflozin improves FAO and attenuates ferroptosis of RTECs via FOXA1-CPT1A axis in diabetic kidney disease.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

Dysregulation of cell cycle, proliferation, and autophagy plays a pivotal role in diabetic kidney disease. In this study, we assessed urinary excretion of molecular regulators of these processes that mediate their effects via the PI3K/AKT/mTOR pathway in subjects with long-term type 2 diabetes (T2D) and different patterns of chronic kidney disease (CKD). We included 140 patients with T2D and 20 non-diabetic individuals in a cross-sectional study. Urinary PTEN, Beclin-1, sirtuin 1 (SIRT1), Klotho, fibroblast growth factor 21 (FGF21), and connective tissue growth factor (CTGF) were assessed using ELISA. Patients with T2D, when compared to control, demonstrated increased excretion of PTEN, Beclin-1, SIRT1, FGF21, CTGF, and decreased urinary Klotho (all p < 0.05). In the diabetic group, PTEN, FGF21, and CTGF were significantly higher in patients with declined renal function, while Klotho was lower in those with elevated albuminuria. FGF21 and PTEN correlated inversely with the estimated glomerular filtration rate. There was a negative correlation between Klotho and urinary albumin-to-creatinine ratio. In multivariate models, Klotho and PTEN were associated with albuminuric CKD independently. The results provide further support for the role of PTEN, BECN1, FGF21, Klotho, and CTGF in development albuminuric and non-albuminuric CKD in diabetes.

Autophagy is an essential quality control mechanism for maintaining organellar functions in eukaryotic cells. Defective autophagy in pancreatic beta cells has been shown to be involved in the progression of diabetes through impaired insulin secretion under glucolipotoxic stress. The underlying mechanism reveals the pathologic role of the hyperactivation of mechanistic target of rapamycin (mTOR), which inhibits lysosomal biogenesis and autophagic processes. Moreover, accumulating evidence suggests that oxidative stress induces Ca2+ depletion in the endoplasmic reticulum (ER) and cytosolic Ca2+ overload, which may contribute to mTOR activation in perilysosomal microdomains, leading to autophagic defects and β-cell failure due to lipotoxicity. This review delineates the antagonistic regulation of autophagic flux by mTOR and AMP-dependent protein kinase (AMPK) at the lysosomal membrane, and both of these molecules could be activated by perilysosomal calcium signaling. However, aberrant and persistent Ca2+ elevation upon lipotoxic stress increases mTOR activity and suppresses autophagy. Therefore, normalization of autophagy is an attractive therapeutic strategy for patients with β-cell failure and diabetes.

Disturbance in metabolism and inflammation are the main causes of kidney injury in patients with late stage diabetic nephropathy (DN). Here, we explored whether autophagy was activated in mice with late stage DN and whether it was associated with disturbance in metabolism and inflammation.

In total, mice were divided into the control group (db/m) and DN group (db/db). Mice were raised for 7 months, and their biochemical indices were measured. Subsequently, their kidneys were collected to detect autophagy and the related nutrient-sensing and inflammatory signaling pathways in late stage DN.

The expression levels of autophagy markers LC3-I and LC3-II were significantly increased in mice with late stage DN, whereas that of autophagy flux marker P62 was significantly decreased, indicating activation of autophagy. Concurrently, mechanistic target of rapamycin was highly expressed as a cellular nutrient-sensing and energy regulator in mice with late stage DN. Additionally, the expression levels of markers of nutrient-sensing signaling pathways adenosine monophosphate-activated protein kinase (AMPK) were increased markedly in mice with late stage DN. Additionally, the expression levels of the marker of nutrient-sensing signaling pathways silent information regulator T1 (SIRT1), the marker of inflammatory signaling pathways high mobility group box protein 1 (HMGB1), and interferon regulatory factor 3 (IRF3) were significantly increased in mice with late stage DN.

The findings of our study indicate that autophagy activation in late stage DN may interfere with nutrient-sensing and inflammatory signaling pathways involving AMPK, SIRT1, HMGB1, and IRF3.

Diabetic kidney disease (DKD), or diabetic nephropathy (DN), is one of the most prevalent complications of type 2 diabetes mellitus (T2DM) and causes severe burden on the general welfare of T2DM patients around the world. While several new agents have shown promise in treating this condition and potentially halting the progression of the disease, more work is needed to understand the complex regulatory network involved in the disorder. Recent studies have provided new insights into the connection between autophagy, a physiological metabolic process known to maintain cellular homeostasis, and the pathophysiological pathways of DKD. Typically, autophagic activity plays a role in DKD progression mainly by promoting an inflammatory response to tissue damage, while both overactivated and downregulated autophagy worsen disease outcomes in different stages of DKD. This correlation demonstrates the potential of autophagy as a novel therapeutic target for the disease, and also highlights new possibilities for utilizing already available DN-related medications. In this review, we summarize findings on the relationship between autophagy and DKD, and the impact of these results on clinical management strategies.

The single and combined effects of short-term selenium (Se) deficiency and T-2 toxin-induced kidney pathological injury through the MMPs/TIMPs system were investigated. Forty-eight rats were randomly divided into control, 10 ng/g T-2 toxin, 100 ng/g T-2 toxin, Se-deficient, 10 ng/g T-2 toxin and Se deficiency combined, and 100 ng/g T-2 toxin and Se deficiency combined groups for a 4-week intervention. The kidney Se concentration was measured to evaluate the construction of animal models of Se deficiency. Kidney tissues were analyzed by hematoxylin-eosin staining, Masson staining, and transmission electron microscope to observe the pathological changes, the severity of kidney fibrosis, and ultrastructural changes, respectively. Meanwhile, quantitative polymerase chain reaction and immunohistochemical staining were used to analyze the gene and protein expression levels of matrix metallopeptidase 2/3 (MMP2/3) and tissue inhibitor of metalloproteinase 1 (TIMP1). The results showed that short-term Se deficiency and T-2 toxin exposure can cause kidney injury through tubular degeneration and even lead to kidney fibrosis. And the combination of T-2 toxin and Se deficiency had a synergistic effect on the kidney. A dose-response effect of the T-2 toxin was also observed. At the gene and protein levels, the expression of MMP2/3 in the intervention group increased, while the expression of TIMP1 decreased compared with the control group. In conclusion, short-term Se deficiency and T-2 toxin exposure might lead to injury and even the development of fibrosis in the kidneys, and combined intervention can increase the severity with a dose-dependent trend. MMP2/3 and TIMP1 likely play a significant role in the development of kidney fibrosis.

Diabetic nephropathy (DN) affects around 40% of people with diabetes, the final outcome of which is end-stage renal disease. The deficiency of autophagy and excessive oxidative stress have been found to participate in the pathogenesis of DN. Sinensetin (SIN) has been proven to have strong antioxidant capability. However, the effect of SIN on DN has not been studied. We examined the effect of SIN on cell viability and autophagy in the podocyte cell line, MPC5 cells, treated with high glucose (HG). For in vivo studies, DN mice models were established by intraperitoneal injected with streptozotocin (40 mg/kg) for 5 consecutive days and fed with a 60% high-fat diet, and SIN was given (10, 20, and 40 mg/kg) for 8 weeks via intraperitoneal injection. The results showed that SIN could protect MPC5 cells against HG-induced damage and significantly improve the renal function of DN mice. Moreover, SIN remarkably restored the autophagy activity of MPC5 cells which was inhibited under HG conditions. Consistent with this, SIN efficiently improved autophagy in the kidney tissue of DN mice. In brief, our findings demonstrated the protective effect of SIN on DN via restoring the autophagic function, which might provide a basis for drug development.

Type II diabetes mellitus (T2DM) is a chronic metabolic disease characterized by prolonged hyperglycemia and insulin resistance (IR). Its incidence is increasing annually, posing a significant threat to human life and health. Consequently, there is an urgent requirement to discover effective drugs and investigate the pathogenesis of T2DM. Autophagy plays a crucial role in maintaining normal islet structure. However, in a state of high glucose, autophagy is inhibited, resulting in impaired islet function, insulin resistance, and complications. Studies have shown that modulating autophagy through activation or inhibition can have a positive impact on the treatment of T2DM and its complications. However, it is important to note that the specific regulatory mechanisms vary depending on the target organ. This review explores the role of autophagy in the pathogenesis of T2DM, taking into account both genetic and external factors. It also provides a summary of reported chemical drugs and traditional Chinese medicine that target the autophagic pathway for the treatment of T2DM and its complications.

Sodium-glucose cotransport protein 2 (SGLT2) inhibitors, a new type of glucose-lowering drug, have been well proved in several clinical studies for their glucose-lowering and nephroprotective effects, and the nephroprotective effects include both indirect effects of metabolic improvement and direct effects, independent of glucose-lowering effects.

In patients with diabetic kidney disease (DKD), several studies have demonstrated the potential nephroprotective mechanisms of SGLT2 inhibitors, and evidence of nephroprotective mechanisms in the non-DKD population is accumulating. Although the nephroprotective mechanism of SGLT2 inhibitors has not been fully elucidated, several laboratory studies have illustrated the mechanism underlying the effects of SGLT2 inhibitors at various aspects.

The purpose of this article is to review the mechanism of nephroprotective effect of SGLT2 inhibitors and to look forward to promising research in the future.

Diabetic kidney disease (DKD) is a prevalent complication of diabetes and a major secondary factor leading to end-stage renal disease. The kidney, a vital organ, is composed of a heterogeneous group of intrinsic cells, including glomerular endothelial cells, podocytes, mesangial cells, tubular epithelial cells, and interstitial fibroblasts. In the context of DKD, hyperglycemia elicits direct or indirect injury to these intrinsic cells, leading to their structural and functional changes, such as cell proliferation, apoptosis, and transdifferentiation. The dynamic remodeling of intrinsic cells represents an adaptive response to stimulus during the pathogenesis of diabetic kidney disease. However, the persistent stimulus may trigger an irreversible remodeling, leading to fibrosis and functional deterioration of the kidney. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of hypoglycemic drugs, exhibit efficacy in reducing blood glucose levels by curtailing renal tubular glucose reabsorption. Furthermore, SGLT2 inhibitors have been shown to modulate intrinsic cell remodeling in the kidney, ameliorate kidney structure and function, and decelerate DKD progression. This review will elaborate on the intrinsic cell remodeling in DKD and the underlying mechanism of SGLT2 inhibitors in modulating it from the perspective of the renal intrinsic cell, providing insights into the pathogenesis of DKD and the renal protective action of SGLT2 inhibitors.

We have performed a systematic review of studies reporting on the renal effects of SGLT2 inhibitors in rodent models of diabetes. In 105 studies, SGLT2 inhibitors improved not only the glycemic control but also various aspects of renal function in most cases. These nephroprotective effects were similarly reported whether treatment with the SGLT2 inhibitor started concomitant with the onset of diabetes (within 1 week), early after onset (1-4 weeks) or after nephropathy had developed (>4 weeks after onset) with the latter probably having the greatest translational value. They were observed across various animal models of type 1 and type 2 diabetes/obesity (4 and 23 models, respectively), although studies in the type 2 diabetes model of db/db mice more often had negative data than in other models. Among possibly underlying pathophysiological mechanisms of nephroprotection, treatment with SGLT2 inhibitors had beneficial effects on lipid metabolism, blood pressure, glomerulosclerosis as well as renal tubular fibrosis, apoptosis, oxidative stress, and inflammation. These pathomechanisms highly influence atherosclerosis and renal health, which are two major factors that lead to an enhanced mortality in patients with diabetes and/or chronic kidney disease. Interestingly, renal SGLT2 inhibitor effects did not always correlate with those on glucose homeostasis, particularly in a limited number of direct comparative studies with other anti-diabetic treatments, indicating that nephroprotection may at least partly occur by mechanisms other than improving glycemic control. Our analyses did not provide evidence for different nephroprotective efficacy between SGLT2 inhibitors. Importantly, only four of 105 studies reported on female animals, and none provided direct comparative data between sexes. We conclude that more data on female animals and more direct comparative studies with other anti-diabetic compounds and combinations of treatments are needed.

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized the role of renal tubular injury in the pathogenesis of DKD. Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER stress, inflammation, EMT and programmed cell death, have been shown to induce renal tubular injury and contribute to the progression of DKD. Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence therapies, mineralocorticoid receptor antagonists, and stem cell therapies have demonstrated their potential to alleviate renal tubular injury in DKD. This review will provide insights into the latest research on the mechanisms and treatments of renal tubular injury in DKD.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aβ42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3β. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Empagliflozin, a selective inhibitor of Na+-glucose cotransporter-2, has been reported to exert anti-inflammatory and anti-fibrotic effects in addition to autophagy modulation. Addressing the role of autophagy in allergic asthma revealed controversial results. The potential effect of empagliflozin treatment on airway inflammation and remodelling as well as autophagy modulation in a murine model of allergic asthma was investigated. Over a 7-week period, male BALB/c mice were sensitized and challenged by intraperitoneal injection and inhalation of ovalbumin, respectively. Animals were treated with empagliflozin (10 mg/kg; orally) and/or rapamycin (an autophagy inducer; 4 mg/kg; intraperitoneally) before every challenge. Methacholine-induced airway hyperresponsiveness was evaluated one day after the last challenge. After euthanasia, serum, bronchoalveolar lavage fluid, and lung tissues were collected for biochemical, histopathological, and immunohistochemical assessment. Results revealed that empagliflozin decreased airway hyperresponsiveness, serum ovalbumin-specific immunoglobulin E, and bronchoalveolar lavage total and differential leukocytic counts. Levels of inflammatory and profibrotic cytokines (IL-4, IL-5, IL-13, IL-17, and transforming growth factor-β1) were all inhibited. Moreover, empagliflozin preserved pulmonary microscopic architecture and alleviated bronchiolar epithelial thickening, goblet cell hyperplasia, fibrosis and smooth muscle hypertrophy. These effects were associated with inhibition of ovalbumin-activated autophagic flux, as demonstrated by decreased LC3B expression and LC3BII/I ratio, as well as increased P62 expression. However, the therapeutic potential of empagliflozin was inhibited when rapamycin was co-administered. In conclusion, this study demonstrates that empagliflozin has immunomodulatory, anti-inflammatory, and anti-remodelling properties in ovalbumin-induced allergic asthma and suggests that autophagic flux inhibition may play a role in empagliflozin's anti-asthmatic effects.

Nutritional and pharmacological therapies represent the basis for non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features and, in certain cases, they also have a synergic action. For instance, dietary sodium restriction enhances the anti-proteinuric and anti-hypertensive effects of RAAS inhibitors, low protein intake reduces insulin resistance and enhances responsiveness to epoetin therapy, and phosphate restriction cooperates with phosphate binders to reduce the net phosphate intake and its consequences on mineral metabolism. It can also be speculated that a reduction in either protein or salt intake can potentially amplify the anti-proteinuric and reno-protective effects of SGLT2 inhibitors. Therefore, the synergic use of nutritional therapy and medications optimizes CKD treatment. Quality of care management is improved and becomes more effective when compared to either treatment alone, with lower costs and fewer risks of unwanted side effects. This narrative review summarizes the established evidence of the synergistic action carried out by the combination of nutritional and pharmacological treatments, underlying how they are not alternative but complementary in CKD patient care.

The management of diabetes and renal failure is changing thanks to the appearance of new drugs such as glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i) that have benefits in terms of survival and cardiorenal protection. Based on the potential mechanisms of GLP1-RA, kidney transplant recipients (KTRs) could benefit from their effects. However, high-quality studies are needed to demonstrate these benefits, in the transplant population, especially those related to cardiovascular benefits and renal protection. Studies with SGLT2i performed in KTRs are much less potent than in the general population and therefore no benefits in terms of patient or graft survival have been clearly demonstrated in this population to date. Additionally, the most frequently observed side effects could be potentially harmful to this population profile, including severe or recurrent urinary tract infections and impaired kidney function. However, benefits demonstrated in KTRs are in line with a known potential effects in cardiovascular and renal protection, which may be essential for the outcome of transplant recipients. Better studies are still needed to confirm the benefits of these new oral antidiabetics in the renal transplant population. Understanding the characteristics of these drugs may be critical for KTRs to be able to benefit from their effects without being damaged. This review discusses the results of the most important published studies on KTRs with GLP1-RA and SGLT2i as well as the potential beneficial effects of these drugs. Based on these results, approximate suggestions for the management of diabetes in KTRs were developed.

Autophagy is essential in regulating the turnover of macromolecules via removing damaged organelles, misfolded proteins in various tissues, including liver, skeletal muscles, and adipose tissue to maintain the cellular homeostasis. In these tissues, a specific type of autophagy maintains the accumulation of lipid droplets which is directly related to obesity and the development of insulin resistance. It appears to play a protective role in a normal physiological environment by eliminating the invading pathogens, protein aggregates, and damaged organelles and generating energy and new building blocks by recycling the cellular components. Ageing is also a crucial modulator of autophagy process. During stress conditions involving nutrient deficiency, lipids excess, hypoxia etc., autophagy serves as a pro-survival mechanism by recycling the free amino acids to maintain the synthesis of proteins. The dysregulated autophagy has been found in several ageing associated diseases including type 2 diabetes (T2DM), cancer, and neurodegenerative disorders. So, targeting autophagy can be a promising therapeutic strategy against the progression to diabetes related complications. Our article provides a comprehensive outline of understanding of the autophagy process, including its types, mechanisms, regulation, and role in the pathophysiology of T2DM and related complications. We also explored the significance of autophagy in the homeostasis of β-cells, insulin resistance (IR), clearance of protein aggregates such as islet amyloid polypeptide, and various insulin-sensitive tissues. This will further pave the way for developing novel therapeutic strategies for diabetes-related complications.

Diabetes mellitus is a major public health issue that affected 537 million people worldwide in 2021, a number that is only expected to increase in the upcoming decade. Diabetes is a systemic metabolic disease with devastating macro- and microvascular complications. Endothelial dysfunction is a key determinant in the pathogenesis of diabetes. Dysfunctional endothelium leads to vasoconstriction by decreased nitric oxide bioavailability and increased expression of vasoconstrictor factors, vascular inflammation through the production of pro-inflammatory cytokines, a loss of microvascular density leading to low organ perfusion, procoagulopathy, and/or arterial stiffening. Autophagy, a lysosomal recycling process, appears to play an important role in endothelial cells, ensuring endothelial homeostasis and functions. Previous reports have provided evidence of autophagic flux impairment in patients with type I or type II diabetes. In this review, we report evidence of endothelial autophagy dysfunction during diabetes. We discuss the mechanisms driving endothelial autophagic flux impairment and summarize therapeutic strategies targeting autophagy in diabetes.