CD44-Positive Glomerular Parietal Epithelial Cells in a Mouse Model of Calcineurin Inhibitors-Induced Nephrotoxicity

Abstract

Background/Aims: Calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus are immunosuppressants that are frequently used as “key drugs” in the fields of transplantation, steroid resistance, refractory nephrotic syndrome, and autoimmune disease. However, long-term CNI use causes nephrotoxicity, the features of which are arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS). We investigated whether FSGS in CNI-induced nephrotoxicity is associated with CD44-positive glomerular parietal epithelial cells (PECs), which play a significant role in experimental and human FSGS pathogenesis. Methods: We utilized the mouse model of CsA-induced nephrotoxicity, as well as controls. Histopathological and functional data were sequentially collected from 1 to 25 weeks after CsA injection. Glomerular expression of CD44 was immunohistochemically evaluated, as were markers for glomerular podocytes and PECs. Results: Glomerular CD44 expression occurred from 2 weeks after CsA injection and gradually increased in the CsA group. CD44-positive glomerular cells showed coexpression of claudin-1 (PEC marker) but not of synaptopodin (podocyte marker). From 20 weeks after CsA injection, the cells formed a bridge between Bowman’s capsule and the capillary tuft. These features are compatible with those of activated PECs, in which increased foot process effacement leads to bridge formation, and subsequently to an increase in glomerulosclerosis and a decrease in the expression of podocyte markers from 20 weeks. Conclusion: CD44-positive (activated) PECs reflect extremely early podocyte injury in the progression of FSGS formation and may be a good marker for early detection of CNI-induced nephrotoxicity.

Biphasic MIF and SDF1 expression during podocyte injury promote CD44-mediated glomerular parietal cell migration in focal segmental glomerulosclerosis

“…Although activated PECs generally show cuboidal or hyperplastic features, PECs expressing CD44 in the early stage revealed a flat shape without hyperplasia. This finding is consistent with previous reports showing CD44 in PECs de novo as an earlier marker of FSGS in humans and a mouse model of calcineurin inhibitor nephropathy in which apparent sclerotic lesions were unidentified (14,40). In our model, CD44-positive cells subsequently increased in the vicinity of podocyte loss.…”

Renal progenitor cells modulated by angiotensin II receptor blocker (ARB) medication and differentiation towards podocytes in anti-thy1.1 nephritis

“…Among the hierarchical subpopulations of parietal epithelial cells (PECs), renal progenitor cells, defined as cells that only express stem cell proteins and not podocyte markers, seem to be the most promising future therapeutic method for nephritis (23,31). This subset of PECs shows the potential capacity to differentiate into a transitional state expressing both stem cells and podocyte markers (32,33) and then into terminal podocytes at the vascular pole (VP) expressing only podocyte proteins (34,35). Appropriate therapeutic methods are able to modulate the differentiation of renal progenitor cells towards podocytes (36,37).…”

Traditional Chinese Medicine in Treating Primary Podocytosis: From Fundamental Science to Clinical Research

“…The non-immune effects of CNIs are nephrotoxic, including tubular atrophy, interstitial inflammation, podocyte damage, and hyaline hyperplasia of arterioles ( Gooch et al, 2017 ). A study found that cyclosporine A-induced expression of CD44 in mice increased with increasing doses, and the foot process, balloon adhesion, and segmental sclerosis in the glomerulus disappeared ( Hayashi et al, 2019 ).…”