Dynamics of hyaluronan, CD44, and inflammatory cells in the rat kidney after ischemia/reperfusion injury

Abstract

Ischemia/reperfusion (I/R) injury in the kidney involves hemodynamic and cellular dysfunctions as well as leukocyte infiltration. Functional recovery occurs via cell proliferation and/or migration. To determine the roles of hyaluronan (HA) and its main receptor CD44 in renal postischemic processes, we compared their localization and expression with that of neutrophils, macrophages, and PCNApositive (regenerative) cells as characterized by immunohistochemistry, up to 28 days after I/R in uninephrectomized rats. Observations covered all kidney zones, i.e. cortex (C), outer and inner stripes of outer medulla (OSOM, ISOM), and inner medulla (IM). In controls, HA was localized to the interstitium of IM and ISOM, and CD44 was mostly present on the basolateral membranes of collecting ducts in ISOM, the thin descending limb of Henle's loop and macula densa cells. After I/R, HA and CD44 staining appeared in C and OSOM at 12 h and persisted throughout the regenerative period, i.e. until day 7. Thereafter, they regressed but remained associated with remodeling areas. CD44 expression was found de novo on the apical pole of regenerating, not fully differentiated tubular cells and on some interstitial cells. It was prominent on all infiltrating neutrophils, as soon as 2 h post-I/R, and on 30% of the macrophages, including those in late HA-rich inflammatory granulomas. CD44 is probably involved in early leukocyte infiltration, in tubular regeneration, and in macrophage activity, while HA modifies the physico-chemical environment of interstitial and migrating cells. Based on its presence in remodeling areas, the HA-CD44 pair may be implicated in persistent postichemic inflammation as observed in chronic allograft nephropathy.

CD44-Positive Cells and Hyaluronan are a Hallmark of a Rat Model of Aristolochic Acid Nephropathy

“…Both markers were tightly linked to the areas of TI lesions, suggesting a crosstalk between CD44 and HA, and between these markers and the AAN lesions. CD44 has been associated with regenerating cells in the liver and kidney [8,10,12,20,21] but from the results of our study there is no sign that a lack of CD44 might be involved in the poor tubular regeneration.…”

“…The frequency of CD44 or CD133-positive cells in the interstitial spaces was evaluated by a semi-quantitative analysis as described previously [8]. Briefly, the distribution of positive cells in the interstitium was performed on one section per animal.…”

“…CD44 (mouse anti-rat antibody OX49, Pharmingen), vimentin (chicken anti-vimentin antibody, Chemicon), CD133 (rabbit anti-CD133 antibody, Biorbyt), and a-smooth muscle actin (α-SMA) (mouse anti-α-SMA, DAKO) were detected on paraffin sections using a streptavidin-biotin immunoperoxidase method (ABC method) as detailed in previous publications [3,7,8]. Detection of HA was performed using a biotinylated HA-Binding Protein (HABP, Calbiochem).…”

“…Numerous studies have described the renal accumulation of CD44, an adhesion molecule involved in cell differentiation, and its main ligand, Hyaluronan (HA), a matrix glycosaminoglycan, in various renal diseases such as ischemia-reperfusion, lithiasis, or renal allograft rejection [8][9][10][11][12][13]. CD44 is a glycoprotein involved in cell-cell and cellmatrix interactions, in particular cell migration and tissue repair.…”

Correlation between hyaluronic acid, hyaluronic acid synthase and human renal clear cell carcinoma

“…Furthermore, HA has taken part in the process of occurrence, development and fibrosis in different kinds of nephritis and diabetic nephropathy; HA also makes a difference to the pathologic process of renal ischemia-reperfusion injury and kidney tubular crystallization [9][10][11][12] . Many studies have confirmed that HA plays very important roles in the biological process of many kinds of malignancy such as mammary cancer, gastric cancer, colorectal cancer, ovarian cancer, melanoma, glioma, lung cancer, prostatic cancer and head & neck cancer, etc.…”