Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat

Abstract

Cadmium (Cd) is a nephrotoxic environmental pollutant that causes insidious injury to the proximal tubule that results in severe polyuria and proteinuria. Cystatin C is a low molecular weight protein that is being evaluated as a serum and urinary biomarker for various types of ischemic and nephrotoxic renal injury. The objective of the present study was to determine if cystatin C might be a useful early biomarker of Cd nephrotoxicity. Male Sprague–Dawley rats were given daily injections of Cd for up to 12 weeks. At 3, 6, 9 and 12 weeks, urine samples were analyzed for cystatin C, protein, creatinine, β2 microglobulin and kidney injury molecule-1. The results showed that Cd caused a significant increase in the urinary excretion of cystatin C that occurred 3–4 weeks before the onset of polyuria and proteinuria. Serum levels of cystatin C were not altered by Cd. Immunolabeling studies showed that Cd caused the relocalization of cystatin C from the cytoplasm to the apical surface of the epithelial cells of the proximal tubule. The Cd-induced changes in cystatin C labelling paralleled those of the brush border transport protein, megalin, which has been implicated as a mediator of cystatin C uptake in the proximal tubule. These results indicate that Cd increases the urinary excretion of cystatin C, and they suggest that this effect may involve disruption of megalin-mediated uptake of cystatin C by epithelial cells of the proximal tubule.

Extracellular vesicles from human bone marrow mesenchymal stem cells repair organ damage caused by cadmium poisoning in a medaka model

“…Recently all‐male mouse and rat models have confirmed that exposure to Cd alone can mimic some aspects of pathotoxic phenotype of Cd poisoning reported in humans (Prozialeck et al ; Edwards and Prozialeck ; Prozialeck et al ; Prozialeck et al ; Yamanobe et al ; Prozialeck et al ). However, since Cd was applied at high concentrations in these studies, the results lacked clinical relevance by missing the effect of lower concentrations and chronic Cd exposure, as well as age‐ and sex‐dependent toxicity (Prozialeck et al ; Edwards and Prozialeck ; Prozialeck et al ; Prozialeck et al ; Yamanobe et al ; Prozialeck et al ). Since adult medakas have historically been used for environmental toxicology, they provided an outstanding experimental paradigm (Wittbrodt et al ; Wessely and Obara ; Walter and Obara ).…”

Relevance of megalin receptor injury with nuclear factor‐kappa B upregulation in acute kidney injury induced in rats

“… Group 1 (control group) : normal male rats received saline and served as controls. Group 2 (AKI group) : normal male rats received Cd chloride for 30 days (2.4 mg/(kg day), i.p. ) and served as AKI rat model.…”

“…It harms, fundamentally, the crucial organs of the body. However, its principle vault organ is the kidney as Cd damages its proximal tubular cells …”

“…However, its principle vault organ is the kidney as Cd damages its proximal tubular cells. [6] Toll-like receptors (TLRs) have a main role in the appreciation of exogenous pathogen-associated molecular patterns through the pathogenesis of sepsis-induced acute kidney injury (AKI). [7] Of the famous mammalian Toll-like receptors, TLR2 and TLR4 have established precise care; however, chemokine secretion was found to be harshly reliant on TLR2 and TLR4.…”

“…[14] Also, megalin intervened take-up of nephrotoxins as aprotinin, toxins, aminoglycosides, and chemotherapeutic agents. [15] Moreover, megalin is a receptor for the Proximal Tubular Endothelial Cell (PTEC) take-up of heavy metal complexes through binding of its transporter (protein metallothionein). [16] The might cause tubulointerstitial damage in several pathogenic situations by persuading oxidative stress.…”