Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy
Abstract Hypertensive nephrosclerosis (HN) and Type 2 diabetic nephropathy (T2DN) are the leading causes of chronic kidney disease (CKD). To explore shared pathogenetic mechanisms, we analyzed transcriptomes of kidney biopsies from patients with HN or T2DN. Total RNA was extracted from 10 μm whole k...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-10-01
|
| Series: | Physiological Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.14814/phy2.15825 |
| _version_ | 1797397450804166656 |
|---|---|
| author | Ole Petter Nordbø Lea Landolt Øystein Eikrem Andreas Scherer Sabine Leh Jessica Furriol Terje Apeland Piotr Mydel Hans‐Peter Marti |
| author_facet | Ole Petter Nordbø Lea Landolt Øystein Eikrem Andreas Scherer Sabine Leh Jessica Furriol Terje Apeland Piotr Mydel Hans‐Peter Marti |
| author_sort | Ole Petter Nordbø |
| collection | DOAJ |
| description | Abstract Hypertensive nephrosclerosis (HN) and Type 2 diabetic nephropathy (T2DN) are the leading causes of chronic kidney disease (CKD). To explore shared pathogenetic mechanisms, we analyzed transcriptomes of kidney biopsies from patients with HN or T2DN. Total RNA was extracted from 10 μm whole kidney sections from patients with HN, T2DN, and normal controls (Ctrl) (n = 6 for each group) and processed for RNA sequencing. Differentially expressed (log2 fold change >1, adjusted p < 0.05) genes (DEG) and molecular pathways were analyzed, and selected results were validated by immunohistochemistry (IHC). ELISA on serum samples was performed on a related cohort consisting of patients with biopsy‐proven HN (n = 13) and DN (n = 9), and a normal control group (n = 14). Cluster analysis on RNA sequencing data separated diseased and normal tissues. RNA sequencing revealed that 88% (341 out of 384) of DEG in HN were also altered in T2DN, while gene set enrichment analysis (GSEA) showed that over 90% of affected molecular pathways, including those related to inflammation, immune response, and cell‐cycle regulation, were similarly impacted in both HN and T2DN samples. The increased expression of genes tied to interleukin signaling and lymphocyte activation was more pronounced in HN, while genes associated with extracellular matrix organization were more evident in T2DN. Both HN and T2DN tissues exhibited significant upregulation of genes connected with inflammatory responses, T‐cell activity, and partial epithelial to mesenchymal transition (p‐EMT). Immunohistochemistry (IHC) further confirmed T‐cell (CD4+ and CD8+) infiltration in the diseased tissues. Additionally, IHC revealed heightened AXL protein expression, a key regulator of inflammation and p‐EMT, in both HN and T2DN, while serum analysis indicated elevated soluble AXL levels in patients with both conditions. These findings underline the shared molecular mechanisms between HN and T2DN, hinting at the potential for common therapeutic strategies targeting both diseases. |
| first_indexed | 2024-03-09T01:11:09Z |
| format | Article |
| id | doaj.art-f2b04b1557c248e98bfb3675c6a055b6 |
| institution | Directory Open Access Journal |
| issn | 2051-817X |
| language | English |
| last_indexed | 2024-03-09T01:11:09Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Physiological Reports |
| spelling | doaj.art-f2b04b1557c248e98bfb3675c6a055b62023-12-11T07:16:19ZengWileyPhysiological Reports2051-817X2023-10-011119n/an/a10.14814/phy2.15825Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathyOle Petter Nordbø0Lea Landolt1Øystein Eikrem2Andreas Scherer3Sabine Leh4Jessica Furriol5Terje Apeland6Piotr Mydel7Hans‐Peter Marti8Department of Clinical Medicine University of Bergen Bergen NorwayDepartment of Clinical Medicine University of Bergen Bergen NorwayDepartment of Clinical Science University of Bergen Bergen NorwaySpheromics Kontiolahti FinlandDepartment of Clinical Medicine University of Bergen Bergen NorwayDepartment of Clinical Medicine University of Bergen Bergen NorwayStavanger University Hospital Stavanger NorwayDepartment of Clinical Medicine University of Bergen Bergen NorwayDepartment of Clinical Medicine University of Bergen Bergen NorwayAbstract Hypertensive nephrosclerosis (HN) and Type 2 diabetic nephropathy (T2DN) are the leading causes of chronic kidney disease (CKD). To explore shared pathogenetic mechanisms, we analyzed transcriptomes of kidney biopsies from patients with HN or T2DN. Total RNA was extracted from 10 μm whole kidney sections from patients with HN, T2DN, and normal controls (Ctrl) (n = 6 for each group) and processed for RNA sequencing. Differentially expressed (log2 fold change >1, adjusted p < 0.05) genes (DEG) and molecular pathways were analyzed, and selected results were validated by immunohistochemistry (IHC). ELISA on serum samples was performed on a related cohort consisting of patients with biopsy‐proven HN (n = 13) and DN (n = 9), and a normal control group (n = 14). Cluster analysis on RNA sequencing data separated diseased and normal tissues. RNA sequencing revealed that 88% (341 out of 384) of DEG in HN were also altered in T2DN, while gene set enrichment analysis (GSEA) showed that over 90% of affected molecular pathways, including those related to inflammation, immune response, and cell‐cycle regulation, were similarly impacted in both HN and T2DN samples. The increased expression of genes tied to interleukin signaling and lymphocyte activation was more pronounced in HN, while genes associated with extracellular matrix organization were more evident in T2DN. Both HN and T2DN tissues exhibited significant upregulation of genes connected with inflammatory responses, T‐cell activity, and partial epithelial to mesenchymal transition (p‐EMT). Immunohistochemistry (IHC) further confirmed T‐cell (CD4+ and CD8+) infiltration in the diseased tissues. Additionally, IHC revealed heightened AXL protein expression, a key regulator of inflammation and p‐EMT, in both HN and T2DN, while serum analysis indicated elevated soluble AXL levels in patients with both conditions. These findings underline the shared molecular mechanisms between HN and T2DN, hinting at the potential for common therapeutic strategies targeting both diseases.https://doi.org/10.14814/phy2.15825diabetic nephropathyhypertensive nephropathyinflammationrenal transcriptome |
| spellingShingle | Ole Petter Nordbø Lea Landolt Øystein Eikrem Andreas Scherer Sabine Leh Jessica Furriol Terje Apeland Piotr Mydel Hans‐Peter Marti Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy Physiological Reports diabetic nephropathy hypertensive nephropathy inflammation renal transcriptome |
| title | Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy |
| title_full | Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy |
| title_fullStr | Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy |
| title_full_unstemmed | Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy |
| title_short | Transcriptomic analysis reveals partial epithelial–mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and Type 2 diabetic nephropathy |
| title_sort | transcriptomic analysis reveals partial epithelial mesenchymal transition and inflammation as common pathogenic mechanisms in hypertensive nephrosclerosis and type 2 diabetic nephropathy |
| topic | diabetic nephropathy hypertensive nephropathy inflammation renal transcriptome |
| url | https://doi.org/10.14814/phy2.15825 |
| work_keys_str_mv | AT olepetternordbø transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT lealandolt transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT øysteineikrem transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT andreasscherer transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT sabineleh transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT jessicafurriol transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT terjeapeland transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT piotrmydel transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy AT hanspetermarti transcriptomicanalysisrevealspartialepithelialmesenchymaltransitionandinflammationascommonpathogenicmechanismsinhypertensivenephrosclerosisandtype2diabeticnephropathy |