CD36 is a novel and potential anti‐fibrogenic target in albumin‐induced renal proximal tubule fibrosis

Abstract

Albumin is not only a risk factor for diabetic nephropathy (DN), but also a therapeutic target. Hence, scientists have long sought ways to elucidate the interactions between albumin and diabetic renal tubule fibrosis. CD36, a surface receptor for thrombospondin-1, has been reported to interact with latent transforming growth factor-beta1 (TGF-beta1) and activate its fibrogenic bioactivity. This study elucidates the interactions between CD36 and renal tubule fibrosis. LLC-PK1 cells were applied to represent renal proximal tubule cells. The expression of CD36 was evaluated by flow cytometry. Fibronectin was assayed by Western blot and enzyme-linked immunosorbent assay (ELISA). Bioactive TGF-beta1 was assayed by ELISA. We demonstrated that albumin was shown significantly to inhibit cell growth without affecting hypertrophy status since protein content and cell size remained unaffected under albumin treatment. Moreover, albumin dose-dependently (0, 1, or 10 mg/ml) enhanced the secretion of bioactive TGF-beta1 and fibronectin with the upregulation of CD36. Intriguingly, CD36 siRNA, a potent silencer for CD36 effectively suppressed the albumin-induced increase in CD36, TGF-beta1, and even fibronectin level. Accordingly, albumin is a pro-fibrogenic factor for proximal tubule cells since albumin per se markedly upregulated the expression of TGF-beta1 and fibronectin. Most importantly, CD36 may mediate albumin-induced cellular fibrosis since CD36 siRNA appeared to have anti-fibrosis effects. This work suggests that CD36 is a novel and potential therapeutic target for diabetic renal tubule fibrosis.

CD36 mediates proximal tubular binding and uptake of albumin and is upregulated in proteinuric nephropathies

“…Similar increases in CD36 expression have been observed in LLC-PK 1 porcine PTCs exposed to albumin (43) and in whole kidney homogenates of nephrotic rats (22). Susztak et al (39) reported increased CD36 expression in the kidneys of patients with diabetic nephropathy with a diffuse cellular distribution, very similar to that observed in the nephrotic kidneys in the present study, but no increased expression in the kidneys of patients with FSGS.…”

“…In human diabetic nephropathy, PTC CD36 expression and apoptosis are positively associated (39). Expression of CD36 in PTC is increased by albumin (43) and following exposure to advanced oxidation protein products (AOPPs). Endocytosis of AOPP-modified human serum albumin by PTC is CD36 dependent (21).…”

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

“…50 Blockade of CD36 through RNA silencing in cultured renal proximal tubular cells reduced bioactive TGF-␤1 and fibronectin in the presence of profibrogenic concentrations of albumin. 59 Together, these data suggest that TSP1-mediated activation of latent TGF-␤ is a key factor in diabetic tubulointerstitial fibrosis and proteinuria. The data showing a reduction in renal fibronectin, especially in the interstitium, by LSKL treatment is supportive of a role for TSP1-regulated TGF-␤ activation in tubulointerstitial fibrosis in diabetes.…”

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

“…CD36 has been reported as a receptor of GHS in mediating the cardiovascular action of GH-releasing peptides in the heart (5). It has been reported that CD36 is a novel and potential antifibrogenic target in albumin-induced renal proximal tubule fibrosis (42), and a CD36 synthetic peptide inhibits silica-induced lung fibrosis in mice (34). Our study showed that mRNA expression of CD36 is very low in SHRs and increased to same level of wild-type rats after hexarelin treatment, indicating the involvement of CD36 in the antifibrotic effect of hexarelin.…”