Abstract
Clusterin, a glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease. Here, we investigated the role of clusterin in diabetic nephropathy (DN). In this study, we found that glomerular clusterin expression was increased in both patients with DN and streptozotocin-induced diabetic mice and that it co-localised with the podocyte marker WT1, indicating clusterin is expressed in podocytes. In our in vitro analysis, we found no significant change in CLU mRNA expression in podocytes following stimulation with high glucose and angiotensin II; in contrast, CLU mRNA expression was significantly upregulated following methylglyoxal stimulation. Methylglyoxal treatment also significantly decreased the mRNA expression of the slit diaphragm markers ZO-1 and NEPH1 and significantly increased the mRNA expression of the oxidative stress marker HO-1. Lastly, we showed that pre-incubating podocytes with recombinant human clusterin protein increased podocyte survival, prevented slit diaphragm damage, and reduced oxidative stress‒induced apoptosis following methylglyoxal stimulation. Taken together, our results indicate that glomerular clusterin is upregulated in DN, and this increase in clusterin expression may protect against oxidative stress-induced apoptosis in podocytes, providing a possible new therapeutic target for DN and other kidney diseases.
Highlights
Clusterin, a glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease
These results were supported by analysing CLU mRNA expression in another cohort, which showed significantly higher levels of CLU mRNA in the glomeruli of diabetic nephropathy (DN) patient samples compared to controls (Fig. 1h)
We found that methylglyoxal significantly increased clusterin expression in cultured human podocytes, and that pre-treating podocytes with recombinant human clusterin protein protected against methylglyoxal-induced oxidative stress and apoptosis
Summary
A glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease. In addition to playing a role in protecting against oxidative stress, biotinylated clusterin can bind to podocytes via the LDL receptor, thereby preventing complementinduced cellular damage in membranous glomerulonephritis ( known as membranous nephropathy)[13]. These findings collectively suggest that glomerular clusterin may protect podocytes from cellular damage. Using an autopsy cohort Nakatani et al found that glomerular clusterin protein levels are 2.42-fold higher in ten diabetic patients compared to non-diabetic controls[19] As these studies involved a relatively small number of patients, the role that increased glomerular clusterin expression plays in DN patients remains poorly understood
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