
-   Certain factors which have been observed to regulate CLU expression include NF-kappaB, growth factors, lipopolysaccharide, and several apoptosis-inducing agents such as ionizing radiation and oxidative stress [PMID: 12787065, PMID: 19118032, PMID: 22571949, PMID: 30872998].
-   In unilaterally nephrectomized rats loaded with bovine serum albumin used as a model of proteinuric renal injury, clusterin expression was found to be significantly altered and regulated by NF-kappaB activation [PMID: 18274700].
-   In caki-1 human human renal cell carcinoma (RCC) cells, clusterin promoted growth and invasion in RCC cells in vitro and in vivo through upregulation of S100A4. Targeting of clusterin conferred growth inhibitory and anti-invasive properties in RCC cells in vitro and in vivo through a down-regulation of S100A4 [PMID: 29400663].
-   In caki-1 human human renal cell carcinoma (RCC) cells, CLU knocked-down (CLUi) cells showed reduced migration and invasion in vitro, as well as decreased metastatic potential in experimental metastasis. MMP-9 was downregulated in CLUi cells and levels of activated ERK1/2 correlated with the rich expression of CLU and MMP-9 in caki-1 cells [PMID: 24008723].
-   In human renal cancer cell line 786-O, CLU knockdown induced apoptosis, inhibited the proliferation and migration of 786-O cells, as well as the downregulation gene expression for PI3K/Akt, MAPK and VEGF pathways [PMID: 23670677].
-   There was a significantly positive correlation between HSF1 expression and PD-L1 expression in hepatocellular cancer (HCC) samples and the combination of expressions for HSF1 and PD-L1 served as the signature for predicting prognosis of patients with HCC. Mechanistically, HSF1 upregulated PD-L1 expression by inducing APOJ expression and activating STAT3 signaling pathway in HCC [PMID: 36482717].
-   Thrombin receptor activation in rat glomerular mesangial and glomerular epithelial cells may regulate renal clusterin mRNA levels through protein kinase C [PMID: 9189857].
-   Clusterin is highly expressed in the brain. Extracellular amyloid-beta peptide (Abeta) is thought to trigger toxic signals leading to neurodegeneration. Clusterin binds to Abeta and prevents Abeta aggregation and clusterin promotes Abeta degradation and accelerates Abeta clearance from the brain. Clusterin thus protects neurons from Abeta and loss of clusterin level in the brain is implicated as promoting Alzheimer's disease pathology [PMID: 28396259]. However, it has been argued that the nature of the interaction between Abeta and clusterin is dependent on the clusterin:Abeta ratio and the factor in excess might determine whether clusterin exhibits neuroprotective or neurotoxic properties [PMID: 17412999].

## Summary

The CLU gene, which encodes the clusterin protein, plays a significant role in kidney diseases and toxicities due to its diverse functions in cellular protection, apoptosis regulation, and response to stress [CS: 9]. In cases of renal damage or toxicity, such as those caused by diseases like diabetic nephropathy or toxic events like ischemia-reperfusion injury, the body triggers protective mechanisms to counteract these harmful effects [CS: 8]. CLU expression is upregulated in response to these stressors, a response likely mediated by factors such as NF-kappaB, growth factors, and apoptosis-inducing agents like ionizing radiation and oxidative stress [CS: 8].

Clusterin, the protein product of the CLU gene, then performs several critical functions in response to this upregulation [CS: 9]. As an extracellular chaperone, clusterin prevents the aggregation of non-native proteins, a common occurrence in stressed or damaged cells, thereby maintaining cellular integrity and preventing further damage [CS: 9]. In the context of renal injury, this chaperone function helps to stabilize proteins that might otherwise aggregate and exacerbate cellular dysfunction [CS: 8]. Moreover, clusterin has a dual role in apoptosis regulation: the secretory form (sCLU) acts as an anti-apoptotic molecule [CS: 7], while the nuclear form (nCLU) has pro-apoptotic effects [CS: 7]. In the kidneys, where cell turnover and regeneration are vital for recovery from injury, these opposing roles of clusterin could facilitate the removal of irreparably damaged cells (through nCLU) and the protection of recoverable cells (through sCLU), thus aiding in the overall recovery and maintenance of kidney function [CS: 8].
