Abstract: Kidney development and function rely heavily on growth hormone (GH) and its downstream effector, insulin-like growth factor-I (IGF-I). In type 1 diabetes mellitus (T1DM), elevated GH levels correlate strongly with glomerular injury and proteinuria. Transgenic animal models have further clarified GH's role in diabetic kidney disease (DKD), demonstrating a direct link between elevated GH levels and glomerulosclerosis. Interestingly, because IGF-I transgenic mice escape glomerulosclerosis, evidence suggests a direct pathological contribution by GH itself. Podocytes, which constitute more than 30% of glomerular cells, serve as specialized visceral epithelial cells vital to the permselectivity of the glomerular filtration barrier and maintenance of other glomerular components such as endothelium and mesangium. Since podocytes express the GH receptor (GHR), understanding the direct impact of GH on podocytes is essential to unravel DKD pathology. GH inflicts irreversible podocytopathy by triggering hypertrophy, mitotic catastrophe, and epithelial-mesenchymal transition (EMT), culminating in podocyte loss, glomerulosclerosis, and proteinuria. Mechanistically, these damaging effects are driven by GH-induced ZEB2 expression, reactivation of Notch signaling, and heightened expression of TGF-β1 and TNF-α. Interrupting the GH/GHR cascade, genetically depleting ZEB2, or halting Notch activation effectively prevents this damage, safeguarding both glomerular architecture and overall kidney function. This manuscript provides an overview of aberrations in GH signaling, particularly in T1DM, dissects its cellular and molecular effects on podocytes, and highlights therapeutic approaches to counteract podocytopathy.
Abstract Non-catalytic function of dipeptidyl peptidase-4 (DPP4) plays a crucial role in inflammation and immune regulation in the body; however, its significance in metabolic associated fatty liver disease (MAFLD) remains largely unknown. We sought to examine the effects of Dpp4 disruption on aspects of MAFLD and to elucidate underlying mechanisms. Wild-type (WT), Dpp4-disrupted, and DPP4 inhibitor-treated C57BL/6J male mice were fed a high-fat diet (HFD) for 12 weeks to establish MAFLD. Hepatic steatosis and liver proinflammatory responses were assessed. Furthermore, bone marrow-derived macrophages from different genotypes were co-cultured with mouse hepatocytes to assess their roles in inflammatory and metabolic responses in vitro. Upon HFD feeding, Dpp4-disrupted mice exhibited significantly attenuated hepatic steatosis and inflammation compared to both DPP4 inhibitor-treated and control WT mice. In vitro, Dpp4-deficient macrophages demonstrated a reduced proinflammatory phenotype. Consequently, these macrophages elicited less fat deposition in co-cultured wild-type hepatocytes. Mechanistically, Dpp4 deficiency significantly upregulated the protein abundance of the adenosine 2A receptor (A2AR) while markedly reducing adenosine deaminase (ADA) levels in both liver tissues and bone marrow-derived macrophages. Our results demonstrate that genetic disruption of Dpp4, unlike its pharmacological inhibition, ameliorates MAFLD progression. This protective effect is mediated through a novel non-catalytic mechanism involving the upregulation of A2AR and downregulation of ADA, which collectively inhibit macrophage-driven inflammation.
Abstract David J Mangelsdorf was a senior colleague in the field of nuclear receptors who passed away unexpectedly in 2025. Dr Mangelsdorf and I share the same postdoctoral mentor at the Salk Institute. This article reflects on my scientific interaction with Dr Mangelsdorf, including the details of our research collaborations and how his discovery and early characterization of retinoid X receptor (RXR) and liver X receptor (LXR) receptor positively influence the research in my laboratory and many other laboratories in the nuclear receptor field.
Abstract Background Osteoporotic fracture (OPF) has become a major global public health issue. We aim to investigate the serum expression and fracture risk association of miR-1236 in OPF and its mechanisms in bone metabolism. Methods This study included 83 osteoporosis (OP) patients and 93 OPF patients. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to analyze gene expression levels. Lipofectamine 2000 was used to overexpress or inhibit miR-1236 in hFOB 1.19 human osteoblast cells and human bone marrow-derived mesenchymal stem cells (hBMSCs). Osteogenic differentiation was induced in hFOB 1.19 cells and adipogenic differentiation in hBMSCs. BMP3 was predicted as a target of miR-1236 by TargetScan and validated by dual-luciferase reporter assay. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were used to assess cell proliferation and apoptosis. Results Serum miR-1236 was down-regulated in OPF patients. OPF patients presented elevated serum bone-metabolic markers (β-CTX, P1NP and BMP-3). miR-1236 was correlated with these bone-related markers in OPF patients. In hFOB 1.19 cells, miR-1236 promoted osteogenic differentiation. BMP3 was negatively regulated by miR-1236 and exerted an inhibitory effect on osteogenic differentiation. In hBMSCs, miR-1236 suppressed adipogenic differentiation, whereas BMP3 promoted adipogenic differentiation. Conclusion Serum miR-1236 is decreased in patients with OPF, and is correlated with altered bone-metabolic markers. In-vitro findings demonstrate that miR-1236 promotes osteogenic differentiation and inhibits adipogenic differentiation by targeting BMP3.
Diabetes results from an inflammatory insult to the pancreas. NFκB is a key transcription factor regulating cellular inflammatory responses. Therefore, we hypothesized that inflammatory exposures would acutely activate NFκB in the adult mouse pancreas and in isolated islets, leading to upregulation of target genes associated with inflammation and apoptosis. Mice were exposed to lipopolysaccharide (LPS), and isolated islets were exposed to a cytokine mixture to model a strong pro-inflammatory challenge. NFκB activation was determined by phosphorylation and nuclear translocation of NFκB proteins p65 and p50, dynamics of the inhibitors, IκBα and IκBβ, and the expression of NFκB target genes. NFκB target gene transcription was then correlated with p65 binding at promoter regions. Targeted apoptotic transcriptome changes were also evaluated. Systemic LPS exposure induced pancreatic NFκB activation, as evidenced by IκB oscillations and nuclear translocation of NFκB subunits. In isolated islets, cytokines triggered rapid p65 phosphorylation and DNA binding and increased NFκB target gene expression, with corresponding increases in specific promoter binding. Notably, anti-apoptotic genes were upregulated. These findings demonstrate that acute inflammatory stress activates NFκB in pancreatic tissue and islets, promoting a pro-inflammatory yet anti-apoptotic transcriptional response. Targeting NFκB at specific time points after inflammation may help prevent β-cell injury and diabetes development.
