Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is a progressive disease that affects millions of adults every year. Major risk factors include diabetes, hypertension, and obesity, which affect millions of adults worldwide. CKD is characterized by cellular injury followed by permanent loss of functional nephrons. As injured cells die and nephrons become sclerotic, remaining healthy nephrons attempt to compensate by undergoing various structural, molecular, and functional changes. While these changes are designed to maintain appropriate renal function, they may lead to additional cellular injury and progression of disease. As CKD progresses and filtration decreases, the ability to eliminate metabolic wastes and environmental toxicants declines. The inability to eliminate environmental toxicants such as arsenic, cadmium, and mercury may contribute to cellular injury and enhance the progression of CKD. The present review describes major molecular alterations that contribute to the pathogenesis of CKD and the effects of arsenic, cadmium, and mercury on the progression of CKD.

Keywords: arsenic; cadmium; cellular injury; chronic kidney disease; heavy metals; mercury.

Figure 1

Molecular mechanisms involved in pathogenesis and progression of chronic kidney disease (CKD). CKD is a complex disease that involves dysregulation of multiple physiological processes. This diagram is meant to show the major molecular mechanisms that promote pathogenesis of CKD with the understanding that there are many other mechanisms that may also be involved in this process.

Figure 2

Process of carbamylation. Carbamylation occurs through two primary pathways that converge due to the spontaneous reactivity of isocyanate with lysine residues and the N-termini of nascent polypeptides. The first and predominant pathway is the spontaneous dissociation of urea to cyanate and ammonia. The second pathway is the conversion of thiocyanate and hydrogen peroxide to cyanate under the action of myeloperoxidase. Once cyanate is formed, it is converted into isocyanate, and the spontaneous and irreversible process of carbamylation commences. MPO, myeloperoxidase.

Figure 3

Flowchart summarizing major effects of arsenic (As) exposure in relation to the progression of CKD. As-induced injury is a complex, multifactorial process that cannot be summarized completely in a single figure. Thus, while this figure includes major pathways of As-induced injury, it does not cover all mechanisms and routes of injury.

Figure 4

Schematic to summarize major factors that contribute to progression of CKD following exposure to cadmium (Cd). Additional factors not included here also contribute to Cd-induced progression of CKD.

Figure 5

Flowchart outlining major mechanisms involved in mercury (Hg)-induced progression of CKD. Other factors not specified here also play a role in the progression of CKD induced by exposure to Hg.