Kidney Research and Clinical Practice最新文献

Background: Stem cell-based therapy is one of the tools for acute kidney injury (AKI) treatment. Tonsil tissue is a promising alternative source for the high-yield isolation of mesenchymal stem cells (MSCs). This study was undertaken to investigate the effects of tonsil-derived MSCs (T-MSCs) in animal model of AKI induced by gentamicin (GM).

Methods: Twenty Sprague-Dawley rats were divided into four groups: Control, GM (70 mg/kg/day, intraperitoneal injection for 10 days), GM + T-MSCs (1 × 107 cells, intravenous injection at 1 day after the last vehicle/GM), and T-MSCs. Renal function, apoptosis, and markers of endoplasmic reticulum stress were measured on day 16 after the first vehicle/GM. Oxidative stress was assessed by measuring urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and the expression of glutathione peroxidase (GPx) and catalase. Effects of T-MSCs on GM-induced apoptosis and oxidative stress in NRK cells were also evaluated using a co-culture technique of NRK cells and T-MSC.

Results: In the GM + T-MSCs group, blood urea nitrogen, creatinine, and tubular damage score were lower compared to the GM group. T-MSCs injection decreased apoptotic cells and the expression of Bax, cytochrome c, and cleaved caspase and increased Bcl-2. T-MSC injection decreased urinary 8-OHdG and increased expression of GPx and catalase in the kidneys. Anti-human nuclei and PKH26 staining demonstrated the localization of T-MSCs in the tubules of renal cortex. In-vitro study revealed that T-MSCs or T-MSC-conditioned media ameliorated GM-induced nicotinamide adenine dinucleotide phosphate oxidase-1 expression, hydrogen peroxide generation, and apoptosis of NRK cells.

Conclusion: Our study demonstrated that T-MSCs ameliorated GM-induced AKI by directly incorporating into the damaged renal tubules and exerting antiapoptotic and antioxidative effects.

Background: Tubulointerstitial renal fibrosis is an essential feature of diabetic nephropathy (DN). Pericytes play a critical role in microvascular diseases and renal fibrogenesis. However, the role of pericytes in DN remains unclear. Herein, we aimed to explore the properties and possible mechanisms of pericytes in renal fibrosis in DN.

Methods: We used multiplex immunofluorescence staining to evaluate the location and expression of activated pericytes and to assess capillary dilation and interstitial fibrosis in the kidneys of db/db mice. Pericytes were co-stained for alpha-smooth muscle actin (α-SMA) to determine which ones differentiate into myofibroblasts in db/db mice. Expression of CD34 and platelet-derived growth factor receptor beta (PDGFR-β) was assessed in kidney tissue from patients with DN by immunohistochemical staining.

Results: We found that cell staining for nerve/glial antigen 2 (NG2)+ and PDGFR-β+ was greater in the kidneys of db/db mice than in those of db/m mice. There was impaired pericyte coverage of blood vessels and capillary dilation in the renal interstitium. These changes were accompanied by increased collagen I staining and an increase in the number of pericytes with profibrotic phenotypes, as identified by increased NG2+/PDGFR-β+/α-SMA+ and decreased NG2+/PDGFR-β+/α-SMA- staining. In DN patients, expression of PDGFR-β was stronger and there was loss of CD34 compared with the findings in control patients with minor glomerular lesions.

Conclusion: In this study, we demonstrated that pericyte activation accompanied by peritubular capillary dysfunction and pericytemyofibroblast transition is associated with renal fibrosis in DN.

There is limited evidence to support the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in solid organ transplants (SOTs). This systematic review and meta-analysis aimed to assess the safety and efficacy of GLP-1RAs in this population. PubMed, Embase, and Cochrane databases were a thorough literature search until July 2024 for SOTs with pre- and posttransplant diabetes mellitus (DM). Hemoglobin A1c (HbA1c), weight, and body mass index (BMI) were the primary outcomes. We estimated odds ratios and standardized mean difference (SMD) or mean difference (MD) with 95% confidence interval (CI) for dichotomous and continuous outcomes, respectively. I2 statistics measured heterogeneity. GLP-1RAs were administered to 806 subjects (99.8%) in 16 trials. Median follow-up was 12 months (interquartile range, 1-49 months). The mean age was 57.05 ± 10.24 years, with 64.6% male patients. HbA1c levels (MD, -0.61% [95% CI, -0.82 to -0.40]; p < 0.01, I2 = 72%), weight, and BMI were statistically significantly reduced. Estimated glomerular filtration rate (eGFR; SMD, -0.38 mL/min/1.73 m2 [95% CI, -1.01 to 0.25]; p = 0.24, I2 = 0%), creatinine, and blood pressure did not change significantly. Additionally, total daily insulin dosage, lipid profile, fasting plasma glucose, and urine albumin-to-creatinine ratio and tacrolimus levels (MD, -0.40 ng/mL [95% CI, -0.85 to 0.05]; p = 0.08, I2 = 42%) did not yield statistically significant. GLP-1RAs caused increased nausea and vomiting (13.9%), urinary tract infections (21.1%), and drug discontinuation (13.4%). In SOT recipients, GLP-1RAs significantly reduced HbA1c, weight, and BMI without significantly altering tacrolimus trough levels, eGFR, creatinine, or cardiovascular outcomes. Gastrointestinal side effects were the most common adverse events.

Background: Early-onset diabetes mellitus has a significant lifetime burden and is associated with higher morbidity and mortality. Since insulin resistance is one of the mechanisms of podocyte injury, we aimed to evaluate the effect of albuminuria on newly developed early-onset type 2 diabetes mellitus (T2DM).

Methods: We screened 6,891,399 subjects aged ≥20 and <40 years without a history of prediabetes or diabetes from the Korean National Health Insurance Service database between 2009 and 2012. A multivariate Cox proportional hazard model was used to identify the impact of albuminuria on early-onset T2DM.

Results: Among a total of 5,383,779 subjects, 62,148 subjects (1.2%) developed early-onset diabetes over 7.3 ± 1.2 years. Albuminuria was significantly associated with early-onset T2DM (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.55-1.70) after adjustment for age, sex, anthropometric data, physical exercise status, serum glucose, and total cholesterol. The risk of early-onset T2DM increased more in subjects with more components of metabolic syndrome (MetS). Among each component of MetS, hypertriglyceridemia was prominently associated with early-onset T2DM (aHR, 2.02; 95% CI, 1.81-2.25) in subjects with albuminuria.

Conclusion: Dipstick albuminuria was significantly associated with early-onset T2DM in young adult populations. Close monitoring of albuminuria is warranted for disease risk modification, especially in subjects with MetS.

Aquaporin-2 (AQP2), the water channel protein exclusively expressed in the kidney collecting duct, plays an essential role in water reabsorption and fluid homeostasis. Dysregulation of Aqp2 transcription and changes in protein abundance lead to water balance disorders such as nephrogenic diabetes insipidus or water overload states. Recent studies have revealed that Aqp2 transcription is highly selective, with only 35 of 3,659 genes exhibiting vasopressin-dependent regulation. Two enhancer elements within a CCCTC-binding factor-insulated topologically associating domain containing the Aqp2 gene control this precise regulation. Contrary to earlier assumptions, ChIP-seq analyses have demonstrated that cyclic adenosine monophosphate-responsive element binding protein (CREB) does not bind within 390 kb of the Aqp2 gene body. Instead, the extended transcription factor candidates, including GATA-binding protein 2 (GATA2), GATA3, and NFATc1, working cooperatively with Yes-associated protein (YAP), have been proposed as one of the key regulators of Aqp2 transcription. This review consolidates the current knowledge of Aqp2 gene regulation, focusing on recent transcriptional studies that have improved the understanding of AQP2 expression patterns. This review discusses the complexity of the Aqp2 gene regulation by integrating information from genome-wide analyses and mechanistic studies. Moreover, the findings provide important insights for translational research and represent significant progress in developing therapeutic strategies for water balance disorders.

Background: The efficient allocation of donor kidneys to appropriate candidates is mandated in Korea, with a very long waiting time for deceased donor kidney transplantation (DDKT). This study evaluated the prognostic implications of organ matching using the Korean Kidney Donor Profile Index (K-KDPI) and Korean Estimated Post-Transplant Survival (K-EPTS).

Methods: We analyzed 7,443 DDKT recipients between 2008 and 2022 using national databases: the Korean Network for Organ Sharing and the National Health Insurance Data Sharing Service. Patients were classified into classes 1 (low K-KDPI [<70] to low K-EPTS [<20] score), 2 (low K-KDPI to high K-EPTS [≥20]), 3 (high K-KDPI [≥70] to low K-EPTS), and 4 (high K-KDPI to high K-EPTS). Patient and graft survival rates were compared among the groups.

Results: Compared with class 1, classes 2 and 4 demonstrated a higher risk of graft failure (hazard ratio [HR], 1.94 and 3.04 for classes 2 and 4, respectively). For patient survival, classes 2 (HR, 2.77) and 4 (HR, 4.29) exhibited an increased risk compared with class 1, whereas class 3 (HR, 1.32) did not show significant differences. We developed a predictive model for the survival benefits of DDKT over dialysis based on the K-KDPI and K-EPTS scoring systems.

Conclusion: To enhance efficient utilization, it is desirable to introduce longevity-matching that prioritizes the allocation of donor organs with low K-KDPI to recipients with low K-EPTS. A predictive model of the survival benefits of DDKT over dialysis could guide decisions regarding the acceptance of organ offers.

Background: Lysyl oxidase-like 2 (LOXL2) has been implicated in tissue fibrosis; however, its role in diabetic podocyte injury remains unclear. This study aimed to investigate the contribution of LOXL2 to fibrotic signaling in podocytes under high-glucose conditions and identify its downstream molecular pathways.

Methods: LOXL2 expression was examined in the glomeruli of patients with diabetes using immunofluorescence staining. Human podocytes were cultured under normal or high-glucose conditions, and LOXL2 was silenced using short hairpin RNA. The gene and protein expression of fibrotic markers, autophagy-related proteins, and key signaling molecules were assessed using quantitative real-time polymerase chain reaction and western blotting.

Results: LOXL2 expression was markedly elevated in the glomeruli of patients with diabetes, particularly in podocytes. In vitro, high-glucose levels significantly upregulated LOXL2 and TGF-β messenger RNA expression in podocytes. LOXL2 knockdown suppressed TGF-β expression and reduced the protein levels of collagen I and α-smooth muscle actin. Furthermore, the phosphorylation of Smad2 and expression of Smad4 decreased in LOXL2-deficient cells, indicating that LOXL2 promotes fibrosis via the transforming growth factor-beta (TGF-β)/Smad pathway. In contrast, the LOXL2 knockdown did not significantly affect the expression of autophagy markers (p62, Beclin-1, and LC3A/B) or activation of the p38 MAPK pathway.

Conclusion: LOXL2 is upregulated in diabetic podocytes and contributes to hyperglycemia-induced fibrosis by activating the TGF-β/Smad signaling pathway. These findings suggest that LOXL2 may serve as a potential therapeutic target for preventing or attenuating podocyte injury in patients with diabetic nephropathy.