Glomerular clusterin expression is increased in diabetic nephropathy and protects against oxidative stress-induced apoptosis in podocytes

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.

Investigation of the Mechanism of Complement System in Diabetic Nephropathy via Bioinformatics Analysis

“…We found that VSIG4 expression was higher in DN renal samples and was negatively correlated with GFR (P < 0:001, r = -0:783). CLU is a kind of complement regulatory protein which can bind to C5b-7 and inhibit the generation of membrane attack complex [59] and was found upregulated in the glomerular of both DN patients and streptozotocin-induced diabetic mice [46]. We found that CLU expression was higher in DN renal samples and was negatively correlated with GFR (P = 0:001, r = -0:639).…”

“…The GO enrichment analysis revealed that hub genes were involved in multiple biological processes, including regulation of complement activation, regulation of humoral immune response, humoral immune response, complement activation, regulation of immune effector process, and macrophage activation. The hub genes, such as C1QA, C1QB, C3, CFB, ITGB2, VSIG4, and CLU, can participate in complement cascade [44][45][46][47]. CD163, CD44, CD48, CD52, and CD53 may involve in humoral immune response and macrophage activation [48,49].…”

Bioinformatics Facilitates the use of Microarrays to Identify Potential Markers in Diabetic Nephropathy

“…We found that COL1A2 expression was upregulatedin DN renal tissues, was negatively correlated with GFR (P = 0:017, r = -0:800), and was positively correlated with Scr (P = 0:010, r = 0:607).CLUis a glycoprotein that is expressed in many tissues, including the kidney [59]. He et al found that glomerular CLU is upregulated in both patients with DN and streptozotocin-induced diabetic mice, and overexpressing CLU may protect against oxidative stress-induced apoptosis in podocytes [60]. Moreover, CLU may delay or even halt the progression of DN by modulating Akt-related pathways [61,62].…”

Aminoguanidine Prevents the Oxidative Stress, Inhibiting Elements of Inflammation, Endothelial Activation, Mesenchymal Markers, and Confers a Renoprotective Effect in Renal Ischemia and Reperfusion Injury

“…Several studies demonstrated that CLU has a cytoprotective role against the deleterious effects of oxidants, working as an antioxidant protein [ 53 ]. Recently, it was observed that glomerular CLU is upregulated in diabetic nephropathy and may have a protective effect against oxidative stress-induced apoptosis in podocytes [ 54 ]. Induction of CLU during IRI was proposed as a survival function in response to high levels of oxidative stress through a mechanism involved in survival autophagy [ 55 ].…”