International Journal of Molecular Sciences

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4 pages, 191 KiB

Open AccessEditorial

Special Issue IJMS—Molecular Mechanisms of Diabetic Kidney Disease

by Ligia Petrica

Int. J. Mol. Sci. 2024, 25(2), 790; https://doi.org/10.3390/ijms25020790 - 8 Jan 2024

Viewed by 1186

Abstract

Diabetic kidney disease (DKD), as a major microvascular complication of both type 1 and type 2 diabetes mellitus (DM), accounts for over 40% of patients that reach end-stage renal disease and are referred to renal replacement therapies [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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21 pages, 4959 KiB

Open AccessArticle

Lysophosphatidic Acid Induces Podocyte Pyroptosis in Diabetic Nephropathy by an Increase of Egr1 Expression via Downregulation of EzH2

by Donghee Kim, Ka-Yun Ban, Geon-Ho Lee and Hee-Sook Jun

Int. J. Mol. Sci. 2023, 24(12), 9968; https://doi.org/10.3390/ijms24129968 - 9 Jun 2023

Cited by 8 | Viewed by 2097

Abstract

Podocyte damage and renal inflammation are the main features and pathogenesis of diabetic nephropathy (DN). Inhibition of lysophosphatidic acid (LPA) receptor 1 (LPAR1) suppresses glomerular inflammation and improves DN. Herein, we investigated LPA-induced podocyte damage and its underlying mechanisms in DN. We investigated [...] Read more.

Podocyte damage and renal inflammation are the main features and pathogenesis of diabetic nephropathy (DN). Inhibition of lysophosphatidic acid (LPA) receptor 1 (LPAR1) suppresses glomerular inflammation and improves DN. Herein, we investigated LPA-induced podocyte damage and its underlying mechanisms in DN. We investigated the effects of AM095, a specific LPAR1 inhibitor, on podocytes from streptozotocin (STZ)-induced diabetic mice. E11 cells were treated with LPA in the presence or absence of AM095, and the expression of NLRP3 inflammasome factors and pyroptosis were measured. A chromatin immunoprecipitation assay and Western blotting were performed to elucidate underlying molecular mechanisms. Gene knockdown by transfecting small interfering RNA was used to determine the role of the transcription factor Egr1 (early growth response protein 1) and histone methyltransferase EzH2 (Enhancer of Zeste Homolog 2) in LPA-induced podocyte injury. AM095 administration inhibited podocyte loss, NLRP3 inflammasome factor expression, and cell death in STZ-induced diabetic mice. In E11 cells, LPA increased NLRP3 inflammasome activation and pyroptosis via LPAR1. Egr1 mediated NLRP3 inflammasome activation and pyroptosis in LPA-treated E11 cells. LPA decreased H3K27me3 enrichment at the Egr1 promoter in E11 cells by downregulating EzH2 expression. EzH2 knockdown further increased LPA-induced Egr1 expression. In podocytes from STZ-induced diabetic mice, AM095 suppressed Egr1 expression increase and EzH2/H3K27me3 expression reduction. Collectively, these results demonstrate that LPA induces NLRP3 inflammasome activation by downregulating EzH2/H3K27me3 and upregulating Egr1 expression, resulting in podocyte damage and pyroptosis, which may be a potential mechanism of DN progression. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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14 pages, 2926 KiB

Open AccessArticle

Sitagliptin Mitigates Diabetic Nephropathy in a Rat Model of Streptozotocin-Induced Type 2 Diabetes: Possible Role of PTP1B/JAK-STAT Pathway

by Sarah M. AL-Qabbaa, Samaher I. Qaboli, Tahani K. Alshammari, Maha A. Alamin, Haya M. Alrajeh, Lama A. Almuthnabi, Rana R. Alotaibi, Asma S. Alonazi, Anfal F. Bin Dayel, Nawal M. Alrasheed and Nouf M. Alrasheed

Int. J. Mol. Sci. 2023, 24(7), 6532; https://doi.org/10.3390/ijms24076532 - 31 Mar 2023

Cited by 11 | Viewed by 3157

Abstract

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose [...] Read more.

Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus. This study examined the therapeutic effects of sitagliptin, a dipeptidyl peptidase inhibitor, on DN and explored the underlying mechanism. Male Wistar albino rats (n = 12) were intraperitoneally administered a single dose of streptozotocin (30 mg/kg) to induce diabetes. Streptozotocin-treated and untreated rats (n = 12) were further divided into normal control, normal sitagliptin-treated control, diabetic control, and sitagliptin-treated diabetic groups (n = 6 in each). The normal and diabetic control groups received normal saline, whereas the sitagliptin-treated control and diabetic groups received sitagliptin (100 mg/kg, p.o.). We assessed the serum levels of DN and inflammatory biomarkers. Protein tyrosine phosphatase 1 B (PTP1B), phosphorylated Janus kinase 2 (P-JAK2), and phosphorylated signal transducer activator of transcription (P-STAT3) levels in kidney tissues were assessed using Western blotting, and kidney sections were examined histologically. Sitagliptin reduced DN and inflammatory biomarkers and the expression of PTP1B, p-JAK2, and p-STAT3 (p < 0.001) and improved streptozotocin-induced histological changes in the kidney. These results demonstrate that sitagliptin ameliorates inflammation by inhibiting DPP-4 and consequently modulating the PTP1B-related JAK/STAT axis, leading to the alleviation of DN. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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15 pages, 4049 KiB

Open AccessArticle

Metabolite Profiling of the Gut–Renal–Cerebral Axis Reveals a Particular Pattern in Early Diabetic Kidney Disease in T2DM Patients

by Lavinia Balint, Carmen Socaciu, Andreea Iulia Socaciu, Adrian Vlad, Florica Gadalean, Flaviu Bob, Oana Milas, Octavian Marius Cretu, Anca Suteanu-Simulescu, Mihaela Glavan, Silvia Ienciu, Maria Mogos, Dragos Catalin Jianu and Ligia Petrica

Int. J. Mol. Sci. 2023, 24(7), 6212; https://doi.org/10.3390/ijms24076212 - 25 Mar 2023

Cited by 5 | Viewed by 2276

Abstract

Type 2 diabetes mellitus (T2DM) represents an important microvascular disease concerning the kidney and the brain. Gut dysbiosis and microbiota-derived metabolites may be in relation with early pathophysiological changes in diabetic kidney disease (DKD). The aim of the study was to find new [...] Read more.

Type 2 diabetes mellitus (T2DM) represents an important microvascular disease concerning the kidney and the brain. Gut dysbiosis and microbiota-derived metabolites may be in relation with early pathophysiological changes in diabetic kidney disease (DKD). The aim of the study was to find new potential gut-derived biomarkers involved in the pathogenesis of early DKD, with a focus on the complex interconnection of these biomarkers with podocyte injury, proximal tubule dysfunction, renal and cerebrovascular endothelial dysfunction. The study design consisted of metabolite profiling of serum and urine of 90 T2DM patients (subgroups P1-normoalbuminuria, P2-microalbuminuria, P3-macroalbuminuria) and 20 healthy controls (group C), based on ultra-high-performance liquid chromatography coupled with electrospray ionization-quadrupole-time of flight-mass spectrometry analysis (UHPLC-QTOF-ESI⁺-MS). By multivariate and univariate analyses of serum and urine, which included Partial Least Squares Discriminant Analysis (PLSDA), Variable Importance Plots (VIP), Random Forest scores, One Way ANOVA and Biomarker analysis, there were discovered metabolites belonging to nitrogen metabolic pathway and retinoic acid signaling pathway which differentiate P1 group from P2, P3, C groups. Tyrosine, phenylalanine, indoxyl sulfate, serotonin sulfate, and all-trans retinoic acid express the metabolic fingerprint of P1 group vs. P2, P3, C groups, revealing a particular pattern in early DKD in T2DM patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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13 pages, 613 KiB

Open AccessArticle

Oxidation State in Peritoneal Dialysis in Patients with Type 2 Diabetes Mellitus

by Leonardo Pazarín-Villaseñor, Yessica García-Salas, Francisco Gerardo Yanowsky-Escatell, Fermín Paul Pacheco-Moisés, Jorge Andrade-Sierra, Tannia Isabel Campos-Bayardo, Daniel Román-Rojas, Andrés García-Sánchez and Alejandra Guillermina Miranda-Díaz

Int. J. Mol. Sci. 2023, 24(3), 2669; https://doi.org/10.3390/ijms24032669 - 31 Jan 2023

Cited by 2 | Viewed by 1710

Abstract

End-stage renal disease (ESRD) progression is closely related to oxidative stress (OS). The study objective was to determine the oxidant and antioxidant status in peritoneal dialysis (PD) patients with type 2 diabetes mellitus (DM). An analytical cross-sectional study from the PD program was [...] Read more.

End-stage renal disease (ESRD) progression is closely related to oxidative stress (OS). The study objective was to determine the oxidant and antioxidant status in peritoneal dialysis (PD) patients with type 2 diabetes mellitus (DM). An analytical cross-sectional study from the PD program was carried out with 62 patients, 22 with and 40 without DM. Lipoperoxides (LPO) levels in patients with DM, 3.74 ± 1.09 mM/L, and without DM, 3.87 ± 0.84 mM/L were found to increase compared to healthy controls (HC) 3.05 ± 0.58 mM/L (p = 0.006). The levels of the oxidative DNA damage marker (8-OH-dG) were found to be significantly increased in patients with DM, 1.71 ng/mL (0.19–71.92) and without DM, 1.05 ng/mL (0.16–68.80) front to 0.15 ng/mL (0.15–0.1624) of HC (p = 0.001). The antioxidant enzyme superoxide dismutase (SOD) activity was found to be significantly increased in patients with DM, 0.37 ± 0.15 U/mL, and without DM, 0.37 ± 0.17 compared to HC, 0.23 ± 0.05 U/mL (p = 0.038). The activity of the enzyme glutathione peroxidase (GPx) showed a significant increase (p < 0.001) in patients with DM, 3.56 ± 2.18 nmol/min/mL, and without DM, 3.28 ± 1.46 nmol/min/mL, contrary to the activity obtained in HC, 1.55 ± 0.34 nmol/min/mL. In conclusion, we found an imbalance of oxidative status in patients undergoing PD with and without DM through the significant increase in LPO oxidants and the marker of oxidative damage in DNA. The activity of the antioxidant enzymes SOD and GPx were significantly increased in patients with and without DM undergoing PD, possibly in an attempt to compensate for the deregulation of oxidants. Antioxidant enzymes could be promising therapeutic strategies as a complement to the management of chronic kidney diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

13 pages, 319 KiB

Open AccessArticle

The Influence of the Severity of Early Chronic Kidney Disease on Oxidative Stress in Patients with and without Type 2 Diabetes Mellitus

by Jorge Andrade-Sierra, Leonardo Pazarín-Villaseñor, Francisco Gerardo Yanowsky-Escatell, Elodia Nataly Díaz-de la Cruz, Andrés García-Sánchez, Ernesto Germán Cardona-Muñoz, Francisco Javier Munguía-Galaviz, Alejandra de Alba-Razo and Alejandra Guillermina Miranda-Díaz

Int. J. Mol. Sci. 2022, 23(19), 11196; https://doi.org/10.3390/ijms231911196 - 23 Sep 2022

Cited by 6 | Viewed by 2256

Abstract

Early Chronic Kidney Disease (CKD) is a condition that tends to progress to End-Stage Kidney Disease (ESKD). Early diagnosis of kidney disease in the early stages can reduce complications. Alterations in renal function represent a complication of diabetes mellitus (DM). The mechanisms underlying [...] Read more.

Early Chronic Kidney Disease (CKD) is a condition that tends to progress to End-Stage Kidney Disease (ESKD). Early diagnosis of kidney disease in the early stages can reduce complications. Alterations in renal function represent a complication of diabetes mellitus (DM). The mechanisms underlying the progression of CKD in diabetes could be associated with oxidative and inflammatory processes. This study aimed to evaluate the state of inflammation and oxidative stress (OS) on the progression of CKD in the early stages in patients with and without type 2 diabetes mellitus (T2DM). An analytical cross-sectional study was carried out in patients with CKD in early stages (1, 2, 3) with and without T2DM. The ELISA method determined the expression of pro-inflammatory cytokines IL-6 and TNF-α as well as lipoperoxides (LPO), nitric oxide (NO), and superoxide dismutase activity (SOD). Colorimetric methods determined glutathione peroxidase (GPx) and total antioxidant capacity (TAC). Patients with CKD and T2DM had significantly decreased antioxidant defenses for SOD (p < 0.01), GPx (p < 0.01), and TAC (p < 0.01) compared to patients without T2DM. Consequently, patients with T2DM had higher concentrations of oxidant markers, NO (p < 0.01), inflammation markers, IL-6 (p < 0.01), and TNF-α than patients without T2DM. CKD stages were not related to oxidative, antioxidant, and inflammatory marker outcomes in T2DM patients. Patients without T2DM presented an increase in SOD (p = 0.04) and a decrease in NO (p < 0.01) when the stage of CKD increased. In conclusion, patients with T2DM present higher levels of oxidative and inflammatory markers accompanied by a decrease in antioxidant defense. However, these oxidative status markers were associated with CKD stage progression in patients without T2DM. Thus, NO and SOD markers could help detect the early stages of CKD in patients who have not yet developed metabolic comorbidities such as T2DM. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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18 pages, 1038 KiB

Open AccessReview

What’s New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances

by Kimio Watanabe, Emiko Sato, Eikan Mishima, Mariko Miyazaki and Tetsuhiro Tanaka

Int. J. Mol. Sci. 2023, 24(1), 570; https://doi.org/10.3390/ijms24010570 - 29 Dec 2022

Cited by 31 | Viewed by 8551

Abstract

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid [...] Read more.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists, have advanced, their efficacy is still limited. Thus, a deeper understanding of the molecular mechanisms of DKD onset and progression is necessary for the development of new and innovative treatments for DKD. The complex pathogenesis of DKD includes various different pathways, and the mechanisms of DKD can be broadly classified into inflammatory, fibrotic, metabolic, and hemodynamic factors. Here, we summarize the recent findings in basic research, focusing on each factor and recent advances in the treatment of DKD. Collective evidence from basic and clinical research studies is helpful for understanding the definitive mechanisms of DKD and their regulatory systems. Further comprehensive exploration is warranted to advance our knowledge of the pathogenesis of DKD and establish novel treatments and preventive strategies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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20 pages, 923 KiB

Open AccessReview

Hypoxia-Inducible Factors and Diabetic Kidney Disease—How Deep Can We Go?

by Alina Mihaela Stanigut, Camelia Pana, Manuela Enciu, Mariana Deacu, Bogdan Cimpineanu and Liliana Ana Tuta

Int. J. Mol. Sci. 2022, 23(18), 10413; https://doi.org/10.3390/ijms231810413 - 8 Sep 2022

Cited by 11 | Viewed by 3395

Abstract

Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that [...] Read more.

Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that about 40% of type 2 diabetes patients will develop nephropathy. In the past years, some research found that hypoxia response and hypoxia-inducible factors (HIFs) play critical roles in the pathogenesis of DN. Hypoxia-inducible factors (HIFs) HIF-1, HIF-2, and HIF-3 are the main mediators of metabolic responses to the state of hypoxia, which seems to be the one of the earliest events in the occurrence and progression of diabetic kidney disease (DKD). The abnormal activity of HIFs seems to be of crucial importance in the pathogenesis of diseases, including nephropathies. Studies using transcriptome analysis confirmed by metabolome analysis revealed that HIF stabilizers (HIF-prolyl hydroxylase inhibitors) are novel therapeutic agents used to treat anemia in CKD patients that not only increase endogenous erythropoietin production, but also could act by counteracting the metabolic alterations in incipient diabetic kidney disease and relieve oxidative stress in the renal tissue. In this review, we present the newest data regarding hypoxia response and HIF involvement in the pathogenesis of diabetic nephropathy and new therapeutic insights, starting from improving kidney oxygen homeostasis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Diabetic Kidney Disease)

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