From Humans to Experimental Models: The Cytoprotective Role of Clusterin in the Kidney

Abstract

Clusterin (CLU) is a chaperone-like protein and has been discovered more than thirty years ago; however, its biological significance is still not fully understood. This review aims to summarize the principal observations of CLU roles related to the kidney. In humans, three or more mRNA isoforms of CLU could be expressed due to different translation start sites, but only two forms of CLU protein, secreted (sCLU, isoform 2) and nuclear (nCLU, isoform 1), have been well characterized, whereas there is only sCLU form in mice. In the biopsies of renal tissue from patients, up regulated CLU expression has been found in rejecting kidney transplants or diseased kidneys, and a lower level of serum CLU is correlated with many types of kidney disease in patients. In mice, a deficiency in CLU expression specifically leads to the phenotype of age-dependent chronic glomerular injury -moderate to severe accumulation of the mesangial matrix, becomes more susceptible to ischemia-reperfusion injury (IRI), negatively impacts renal repair after IRI and worsens renal fibrosis after ureteral obstruction. All these observations may imply the biological significance of CLU for the maintenance of the tissue homeostasis in adult kidneys. However, how CLU protects the kidney from injury or by which extracellular and intracellular pathways mediate the cyto-protection of CLU in the kidney has not been well investigated. Understanding of the cyto-protective activities of CLU in the kidney could lead to the development of novel therapeutic strategies for the prevention and/or treatment of kidney injury or diseases. CLU Gene, Isoforms and Cellular LocalizationClusterin (CLU) protein was first discovered more than thirty years ago [1], and a large volume of research has been dedicated to it since -there are more than two thousand publications in Pubmed/NCBI databases when using 'clusterin' as a keyword search criteria today. Human CLU gene (NCBI Gene ID: 1191) is located at chromosome 8p21-p12, and consists of 10 exons, in which the first two exons are alternative (designated 1 and 1') [2]. Thus, CLU gene can be transcribed into at least three mRNA variants (NCBI Reference No.: NM_001831.3; NR_038335.1; NR_045494.1) or perhaps even more [3]. The mRNA isoform 1 is a major form of CLU mRNA, whereas other forms including mRNA isoform 2 collectively count for less than 1% of total CLU mRNA [3]. Two isoforms of CLU proteins have been well characterized; nuclear isoform of CLU (nCLU, isoform 1) containing the nuclear localization signal that is translated due to the splicing at exon 1 and 3 together placing a downstream AUG at exon 3 as the first available translation and lacking of exon 2 [3,4], while pre-secreted isoform of CLU (sCLU) containing the endoplasmic reticulum (ER)-targeting signalencoding in exon 2 [3]. The nCLU is translocated into the nucleus after translation andprobably without glycosylation [3], whereas the pre-secreted sCLU is targeted to ER and Golgi bodies glycosylation and cleavage between Arg-205 and Ser-206 to produc...