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Single-cell RNA sequencing-based identification of novel podocyte injury-associated genes from isolated glomeruli of diabetic db/db mice [RNA-seq]

ABSTRACT: Podocyte injury is a key driver of progression in diabetic kidney disease (DKD). Because podocytes are underrepresented in whole-kidney single-cell RNA sequencing datasets, we performed single-cell RNA sequencing of isolated glomeruli from diabetic db/db mice and control db/m mice to generate a glomerulus-focused transcriptomic dataset. Diabetic glomeruli showed reduced podocyte abundance and extensive transcriptional remodeling. Integration of this in vivo dataset with in vitro analyses of cultured human podocytes exposed to diabetic stimuli identified OPCML, ADM, NELL2, and DHRS3 as candidate genes associated with diabetic podocyte injury. These findings identify OPCML, ADM, and DHRS3 as novel mediators of podocyte injury and potential therapeutic targets for DKD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337565 | GEO | 2026/09/17

REPOSITORIES: GEO

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Single-cell RNA sequencing-based identification of novel podocyte injury-associated genes from isolated glomeruli of diabetic db/db mice [scRNA-seq]

Project description:Podocyte injury is a key driver of progression in diabetic kidney disease (DKD). Because podocytes are underrepresented in whole-kidney single-cell RNA sequencing datasets, we performed single-cell RNA sequencing of isolated glomeruli from diabetic db/db mice and control db/m mice to generate a glomerulus-focused transcriptomic dataset. Diabetic glomeruli showed reduced podocyte abundance and extensive transcriptional remodeling. Integration of this in vivo dataset with in vitro analyses of cultured human podocytes exposed to diabetic stimuli identified OPCML, ADM, NELL2, and DHRS3 as candidate genes associated with diabetic podocyte injury. These findings identify OPCML, ADM, and DHRS3 as novel mediators of podocyte injury and potential therapeutic targets for DKD.

2026-09-17 | GSE337566 | GEO

Puerarin attenuates diabetic kidney injury through interaction with Guanidine nucleotide-binding protein Gi subunit alpha-1 (Gnai1) subunit

Project description:Radix puerariae, a traditional Chinese herbal medication, has been used to treat patients with diabetic kidney disease (DKD). Our previous studies demonstrated that puerarin, the active compound of radix puerariae, improves diabetic podocyte injury in type 1 DKD mice through attenuation of oxidative stress. However, the direct molecular target of puerarin and its underlined mechanisms in DKD remains unknown. In this study, we first confirmed that puerarin also improved DKD in type 2 diabetic mice (db/db). Through RNA-sequencing of isolated glomeruli, we found that differentially expressed genes (DEGs) that were altered in the glomeruli of these diabetic mice but reversed by puerarin treatment were involved mostly in oxidative stress, inflammatory, and fibrosis. Further analysis of these reversed DEGs revealed protein kinase A (PKA) was among the top pathways. By utilizing the drug affinity responsive target stability (DARTS) method combined with mass spectrometry analysis we identified guanine nucleotide-binding protein Gi alpha-1 (Gnai1) as the direct binding partner of puerarin. Gnai1 is an inhibitor of cAMP production which is known to have protection against podocyte injury. Searching Nephroseq datasets revealed that Gnai1 expression increased in the glomeruli of human DKD. In vitro, we showed that puerarin not only interacted with Gnai1 but also increased cAMP production in human podocytes and kidney cortex of mice treated with peurarin. Puerarin also enhanced CREB phosphorylation, a downstream transcription factor of cAMP/PKA. Overexpression of CREB reduced high glucose-induced podocyte apoptosis. We conclude that the renal protective effects of puerarin are likely through inhibiting Gnai1 to activate cAMP/PKA/CREB pathway in podocytes.

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Comparison of Glomerular and Podocyte mRNA Profiles in eNOS-/- Diabetic Mice Induced by Streptozotocin

Project description:We compared mRNA profiles of isolated glomeruli versus sorted podocytes between diabetic and control mice. IRG mice crossed with eNOS-/- mice were further bred with podocin-rTTA and TetON-Cre mice to permanently label podocytes before the diabetic injury. Diabetes was induced by injection of streptozotocin. mRNA profiles of isolated glomeruli and sorted podocytes from diabetic and control mice at 10 weeks after induction of diabetes were examined. Consistent with the previous reports, expression of podocyte-specific markers in the glomeruli were down-regulated in the diabetic mice compared to controls. However, these differences disappeared when mRNA levels were corrected for podocyte number per glomerulus. Interestingly, the expression of these markers was not altered in sorted podocytes from diabetic mice, suggesting that the reduced expression of podocyte markers in isolated glomeruli is likely a secondary effect of reduced podocyte number, rather than the loss of differentiation markers. Analysis of the differentially expressed genes in diabetic mice also revealed distinct up-regulated pathways in the glomeruli (mitochondrial function and oxidative stress) and podocytes (actin organization). In conclusion, our data suggest that podocyte-specific gene expression in transcriptome obtained from the whole glomeruli may not represent those of podocytes in the diabetic kidney. We compared mRNA profiles of isolated glomeruli versus sorted podocytes between diabetic and control mice.

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Project description:Podocyte injury is a critical early event in the progression of diabetic kidney disease (DKD), and metabolic reprogramming has emerged as a key determinant of podocyte dysfunction. Although podocytes rely predominantly on glycolysis to maintain their structural and functional integrity, the molecular regulators controlling glycolytic flux in podocytes during DKD remain incompletely understood. Here, we demonstrated that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) was significantly reduced in podocytes from both DKD patients and diabetic mice. Podocyte-specific deletion of PPDPF in mice aggravated albuminuria, glomerular injury, and podocyte injury under diabetic conditions. However, overexpression of PPDPF ameliorated cytoskeletal disorganization and foot process effacement through increasing glycolytic flux and ATP production. Mechanistically, PPDPF competitively bound to WW Domain-containing E3 Ubiquitin Protein Ligase 1 (WWP1) and suppressed WWP1-mediated ubiquitination and degradation of CCCTC-binding factor (CTCF), thereby sustaining phosphoglycerate mutase 1 (PGAM1) transcription and promoting podocyte glycolysis. Notably, PPDPF expression was associated with podocyte loss, serum creatinine and glomerular filtration rate in patients with DKD. Thus, our findings identified PPDPF as a previously unrecognized guardian of podocyte glycolysis and suggest that targeting the PPDPF-dependent metabolic pathway may represent a promising therapeutic strategy for DKD.

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Comparison of Glomerular and Podocyte mRNA Profiles in eNOS-/- Diabetic Mice Induced by Streptozotocin

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Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

Project description:Arctigenin (ATG) is a major component of Fructus Arctii, which as a traditional herbal remedy reduced proteinuria in diabetic patients. However, whether ATG specifically provided renoprotection in DKD was not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via its interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results clearly demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

2019-11-08 | PXD014976 | Pride

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Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

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