Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy

Abstract

<jats:p>Epithelial-to-mesenchymal transition (EMT) is an important mechanism of renal tubulo-interstitial fibrosis in diabetic nephropathy (DN). Inducers of EMT, among others, are transforming growth factor-β<jats:sub>1</jats:sub>(TGF-β<jats:sub>1</jats:sub>) as well as extracellular collagens. In renal cells of diabetic mice and in kidneys of patients with DN, the expression of collagen VIII (gene: Col8α1/α2) is enhanced and characteristic features of DN in streptozotocin (STZ)-induced diabetic Col8α1/α2 knockout-(KO) mice are attenuated compared with diabetic wild-type mice. This study aimed to investigate whether collagen type VIII may influence the induction of EMT. DN was induced in wild-type and Col8α1/α2-KO mice using the established and widely accepted low-dose STZ model [treatment for 5 consecutive days (50 mg/kg)]. Healthy and diabetic mice were analyzed for changes in renal function and the expression of EMT-related genes and proteins. Renal morphology, fibrosis, and various EMT markers were studied in kidneys using immunohistological and molecular biological methods. Knockout of Col8α1/α2 attenuated albuminuria, extracellular matrix production, as well as fibrosis. Furthermore, the kidneys of diabetic Col8α1/α2-KO mice showed a marked reduction in interstitial myofibroblasts, and in tubular cells the inhibition of the expression of epithelial markers as well as the expression of typical mesenchymal markers was reduced. The present study demonstrates that in contrast to diabetic wild-type mice EMT-like changes were attenuated in diabetic Col8α1/α2-KO mice, which indicates that either collagen VIII may be one of the major inducers of EMT-like changes in kidneys of diabetic wild-type mice or/possibly the lack of Col8α1/α2 disrupts TGF-β<jats:sub>1</jats:sub>-induced EMT-like changes.</jats:p>

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“…Even though we used a high dose of STZ (delivered as a single intraperitoneal injection of 150 mg/kg) to establish the diabetic model, our investigations were carried out at 3 and 6 months after the STZ administration; this strategy minimized the potential role of tubular toxicity, but did not eliminate it. Establishing the model by using a repeated injection of low dose STZ (50 mg/kg/day × 5 days) would have been more appropriate [48], and future studies should consider this modeling approach. Second, the STZ-induced diabetes model was established in C57BL/6J mice in the present study.…”

Asiatic acid ameliorates tubulointerstitial fibrosis in mice with ureteral obstruction

“…Abnormal deposition of ECM is one of the main pathological changes observed following UUO, and leads to a decrease in the diffusion of oxygen (23). It also contributes to abnormal intercellular signaling, leading to a vicious cycle of ECM deposition (24,25). In the present study, Masson’s trichrome staining revealed that small quantities of ECM were present in the normal kidneys, predominantly in the glomerular basement membrane and the peritubular blood vessels.…”

Retracted: miR‐124a enhances therapeutic effects of bone marrow stromal cells transplant on diabetic nephropathy‐related epithelial‐to‐mesenchymal transition and fibrosis

“…[1][2][3] Previous studies have reported an inverse correlation between the number of myofibroblasts and renal function in DN patients. During the pathological process, extracellular matrix (ECM) proteins, including a variety of collagens, laminin and fibronectin (FN), accumulate in the mesangium and renal tubulointerstitium, therefore leading to glomerulosclerosis and interstitial fibrosis.…”

“…[1][2][3] Previous studies have reported an inverse correlation between the number of myofibroblasts and renal function in DN patients. 2,4,6,9,10 Podocytes, glomerular epithelial cells, are the sites of one of the origins of matrix-producing myofibroblasts among the bone marrow, tubular epithelium, and vascular endothelium in the diseased kidney. As a source of matrixgenerating fibroblasts, the renal epithelial-to-mesenchymal transition (EMT) has attracted increasing attention.…”