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Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism

ABSTRACT: Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism

PROVIDER: PRJNA1171019 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30939026_1.fastq.gz	Fastqsanger.gz
	SRR30939026_2.fastq.gz	Fastqsanger.gz
	SRR30939027_1.fastq.gz	Fastqsanger.gz
	SRR30939027_2.fastq.gz	Fastqsanger.gz
	SRR30939028_1.fastq.gz	Fastqsanger.gz

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Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism

Project description:SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. To better understand their molecular effects, RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection. Male adult DBA wildtype (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10mg/kg diet) for 2 weeks, and other Akita mice received GLP1R agonist semaglutide (sema; 3nmol/[kg body weight*day], s.c.). Dapa (254±11mg/dL) and Sglt1-KO (367±11mg/dL) but not sema (407±44mg/dL) significantly reduced hyperglycemia in Akita mice (480±33mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (~1%) differentially expressed genes vs. WT (DEGs; adjusted p<0.1) including downregulation of anionic transport, unsaturated fatty acid and carboxylic acid metabolism. Dapa changed only 2 genes in WT but restored 43% of DEGs in Akita, including upregulation of lipid metabolic pathway, carboxylic acid metabolism and organic anion transport. In Akita, sema restored ~10% of DEGs, and Sglt1-KO and dapa were synergistic (restored ~61%) possibly involving additive blood glucose effects (193±15mg/dl). Targeted analysis of transporters and channels (t-test p<0.05) revealed that ~10% of 526 detectable transporters and channels were downregulated by Akita, with ~60% restored by dapa. Dapa, dapa+Sglt1-KO and sema also altered Akita-insensitive genes. Among DEGs in Akita, ~30% were unresponsive to any treatment, indicating potential new targets. In conclusion, SGLT2i restored transcription for multiple metabolic pathways and transporters in SGLT2-positive proximal tubule segments in diabetic mice, with a smaller effect also observed for GLP1R agonism.

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Transcriptomics of S3 segment in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism

Project description:Inhibitors of SGLT2 (SGLT2i) and diabetes enhance glucose delivery and reabsorption in late proximal tubule S3 segments. However, the molecular consequences remain poorly understood. Here we determined transcriptomic changes in S3 segments of male adult DBA wildtype (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) given vehicle or SGLT2i dapagliflozin for 2 weeks, and in Akita mice receiving GLP1R agonist (GLP1RA) semaglutide. RNA sequencing was performed in S3 segments isolated by immunostaining-guided laser-capture-microdissection in deep cortex/outer medulla. Among 19,068 detected annotated genes, 838 genes were differentially expressed by SGLT2i in WT (DEGs; p<0.05) and 1,410 genes in Akita vs. WT. ~34% of SGLT2i-sensitive genes changed in same direction in Akita. Both maneuvers upregulated pathways of cellular proliferation (confirmed by phospho-Ser10 Histone H3 staining) and cellular response to stress, while downregulating pathways of immune/inflammatory response, cytokine production/receptor signaling, and cell adhesion/migration. Both maneuvers also induced unique responses. Unique pathway responses to SGLT2i in WT included increase in DNA dealkylation/demethylation and lysosomal acidification, and reduced valine biosynthesis. Differences in Sglt1-dependency of responses to Akita versus SGLT2i in WT suggested different initiating mechanisms. In Akita mice, inhibition of SGLT2, Sglt1-KO and GLP1R agonism restored 12, 18 and 25% of DEGs, respectively. Akita downregulated whole kidney SGLT1 membrane expression, potentially to limit glucose-induced stress. GLP1RA reduced/restored cellular stress response and proliferation in Akita in S3 segments, associated with enhanced/restored kidney membrane expression of SGLT1. Finally, Akita-sensitive genes unresponsive to any of the 3 maneuvers were identified that may indicate new therapeutic avenues.

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Cell autonomous and non-autonomous effects of constitutive Yap1 activation in distal nephron segments

Project description:The distal convoluted tubule (DCT) and connecting tubule (CNT) are critical for fine-tuning electrolyte reabsorption and maintaining renal homeostasis. While the Hippo pathway effector Yap1 is known to regulate renal development, its specific function in distal nephron segments remains poorly defined. To investigate Yap1 function in the distal nephron, we generated a Cre-inducible Yap1 gain-of-function allele (Col1a1-YAP5SA) and a distal nephron-specific Slc12a3-IRES-Cre to express constitutively active Yap1 in the distal nephron segments. Lineage tracing analysis showed that the Slc12a3Cre targets both DCT and CNT, suggesting that CNT cells arise from Slc12a3+ DCT cells. Constitutive activation of Yap1 in DCT and CNT results in increased proliferation and abnormal migration into adjacent nephron segments. This was accompanied by disrupted expression of DCT/CNT marker genes, loss of apicobasal polarity, and compromised junctional architecture. Unexpectedly, the mutant kidneys showed the downregulation of proximal tubule marker genes and Ren1 and the upregulation of inflammation and injury markers. These findings demonstrate that sustained Yap1 activation in the distal nephron segments impairs epithelial identity and structure, and also induces non–cell-autonomous effects in other nephron segments, particularly the proximal tubule. This highlights the importance of tightly regulated Hippo-Yap signaling in maintaining epithelial integrity and proper nephron segmentation.

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