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- Title
Role of CD44 expressed in renal tubules during maladaptive repair in renal fibrogenesis in an allopurinol‐induced rat model of chronic kidney disease.
- Authors
Matsushita, Kohei; Toyoda, Takeshi; Akane, Hirotoshi; Morikawa, Tomomi; Ogawa, Kumiko
- Abstract
The kidney is a major target organ for the adverse effects of pharmaceuticals; renal tubular epithelial cells (TECs) are particularly vulnerable to drug‐induced toxicity. TECs have regenerative capacity; however, maladaptive repair of TECs after injury leads to renal fibrosis, resulting in chronic kidney disease (CKD). We previously reported the specific expression of CD44 in failed‐repair TECs of rat CKD model induced by ischemia reperfusion injury. Here, we investigated the pathophysiological role of CD44 in renal fibrogenesis in allopurinol‐treated rat CKD model. Dilated or atrophic TECs expressing CD44 in fibrotic areas were collected by laser microdissection and subjected to microarray analysis. Gene ontology showed that extracellular matrix (ECM)‐related genes were upregulated and differentiation‐related genes were downregulated in dilated/atrophic TECs. Ingenuity Pathway Analysis identified CD44 as an upstream regulator of fibrosis‐related genes, including Fn1, which encodes fibronectin. Immunohistochemistry demonstrated that dilated/atrophic TECs expressing CD44 showed decreases in differentiation markers of TECs and clear expression of mesenchymal markers during basement membrane attachment. In situ hybridization revealed an increase in Fn1 mRNA in the cytoplasm of dilated/atrophic TECs, whereas fibronectin was localized in the stroma around these TECs, supporting the production/secretion of ECM by dilated/atrophic TECs. Overall, these data indicated that dilated/atrophic TECs underwent a partial epithelial–mesenchymal transition (pEMT) and that CD44 promoted renal fibrogenesis via induction of ECM production in failed‐repair TECs exhibiting pEMT. CD44 was detected in the urine and serum of APL‐treated rats, which may reflect the expression of CD44 in the kidney. Maladaptive repair of renal tubular epithelial cells (TECs) leads to chronic kidney disease (CKD). Here, pathophysiological role of CD44 expressed in failed‐repair TECs in renal fibrogenesis was investigated using rat model of CKD with allopurinol. Overall results indicated that CD44 promoted renal fibrogenesis via induction of ECM production in failed‐repair TECs exhibiting partial epithelial–mesenchymal transition. CD44 was also detected in the urine and serum of rat model of CKD, indicating potential of CD44 as a CKD biomarker.
- Subjects
KIDNEY tubules; CHRONIC kidney failure; CD44 antigen; ANIMAL disease models; KIDNEYS; REPERFUSION; REPERFUSION injury; FIBRONECTINS
- Publication
Journal of Applied Toxicology, 2024, Vol 44, Issue 3, p455
- ISSN
0260-437X
- Publication type
Article
- DOI
10.1002/jat.4554