Mitochondrial Pathophysiology on Chronic Kidney Disease

Abstract

In healthy kidneys, interstitial fibroblasts are responsible for the maintenance of renal architecture. Progressive interstitial fibrosis is thought to be a common pathway for chronic kidney diseases (CKD). Diabetes is one of the boosters of CKD. There is no effective treatment to improve kidney function in CKD patients. The kidney is a highly demanding organ, rich in redox reactions occurring in mitochondria, making it particularly vulnerable to oxidative stress (OS). A dysregulation in OS leads to an impairment of the Electron transport chain (ETC). Gene deficiencies in the ETC are closely related to the development of kidney disease, providing evidence that mitochondria integrity is a key player in the early detection of CKD. The development of novel CKD therapies is needed since current methods of treatment are ineffective. Antioxidant targeted therapies and metabolic approaches revealed promising results to delay the progression of some markers associated with kidney disease. Herein, we discuss the role and possible origin of fibroblasts and the possible potentiators of CKD. We will focus on the important features of mitochondria in renal cell function and discuss their role in kidney disease progression. We also discuss the potential of antioxidants and pharmacologic agents to delay kidney disease progression.

Keywords: chronic kidney disease (CKD); electron transport phosphorylation (ETC) impairment; epithelial-mesenchymal transition (EMT); fibrosis; mitochondria; oxidative stress (OS).

Figure 1

Epithelial and Mesenchymal transition. After injury, epithelial cells suffered a process called epithelial-mesenchymal transition (EMT), in which cells start expressing mesenchymal markers rather than epithelial markers. A wide number of factors have been pointed to as a potentiator of tubular EMT. The most potent inducer is Transforming growth factor-beta 1 (TGF-β1). Furthermore, signaling pathways that cooperate with TGF-β1 are also considered to be important mediators for EMT and consequently to renal fibrosis, such as Smad family, Renin-angiotensin system (RAS), and Wnt/β-catenin signaling. EMT is a highly coordinated process, characterized by the loss of cell-cell contact leading to cellular destabilization. Then, there is a de novo expression of mesenchymal proteins, such as α-SMA, and where it produced extracellular matrix proteins, including fibronectin, collagen I, and Fibroblast-specific protein 1 (FSP-1.) In the last phase of EMT, fibroblasts are activated and called myofibroblasts. These myofibroblasts share the same place that resident fibroblasts, whose proliferation is increased. This accumulation in the interstitium between tubules culminates in tubulointerstitial fibrosis.

Figure 2

Schematic overview of the major metabolic pathways in renal epithelial cells. Principal substrates used to produce ATP. In renal cells, the uptake of free fatty acids, ketone bodies, glucose, and glutamine lead to increased oxygen consumption and ATP production, through ATP synthase. Glucose, in distal tubules in the healthy kidney, is metabolized to glucose-6-phosphate which is converted into Fructose-1,6-biphosphate. Then, Fructose-1,6-biphosphate is cleaved into two phosphorylated three-carbon compounds glyceraldehyde 3-phosphate and dihydroxyacetone phosphate), known as triose phosphatases. Afterward, glyceraldehyde 3-phosphate is converted into phosphoenolpyruvate and finally into pyruvate. Free fatty acid oxidation is a more efficient substrate to use than glucose in terms of energy production; however, in diabetic nephropathy disease, some complications occurred, i.e., increasing of lipid droplets. Within the cortex, ketones bodies are also a substrate used for ATP production. Glycerol becomes an important gluconeogenic precursor in diabetes. It is broken into glucose-6-phosphate and then be transformed into pyruvate and continues to follow the same path as glucose metabolization. Gluconeogenesis (up dashed arrows), which occurs in proximal tubules cells, needs ATP to produce glucose, which can be synthesized from lactate, and glycerol. Glutamine is degraded and converted to glutamate, which can be transaminated via glutamate-oxaloacetate-transaminase or glutamate-alanine-transaminase, which bot reaction yield α-ketoglutarate, an intermediate of Krebs cycle. Pyruvate resulted from lactate, enters into the mitochondria, and is converted to oxaloacetate. Oxaloacetate, in the cytoplasm of the mitochondria, can be reduced to malate and be exported out and/ or in the cytoplasm. Here, through malate aspartate shuttle (MAS), first, malate is oxidized to oxaloacetate and then converted to phosphoenolpyruvate and subsequently converted to fructose-6-phosphate. After a phosphatase, fructose-6-phosphate is dephosphorylated, which results in glucose-6-phosphate, which then is converted into the release of glucose.

Figure 3

Mitochondrial oxidative phosphorylation and the mechanism of the main antioxidant enzymes present in the kidney. Reducing equivalents (NADH, FADH₂) produced through the Krebs cycle donate electrons to the electron transport system at complex I and complex II. These electrons are subsequently transferred to other electron carriers, including coenzyme Q, complex III, cytochrome C (Cyt C), and complex IV. In complex IV, the oxygen is reduced into water. The donation of electrons provides the energy to pump protons (H⁺), which is responsible for the establishment of the electrochemical proton gradient at the inner mitochondrial membrane. This phenomenon generates the proton motive force that forces the protons back inside the matrix at ATP synthase to regenerate ATP from ADP and Pi. In diabetic nephropathy (DN), the production is reduced. With physiological conditions, some part of the O₂ is converted into reactive oxygen species (ROS), where complexes I and III are considered the principal sites of ROS production. In the kidney, when the electron transport chain and mitochondria functioning is impaired, there is an imbalance between ROS and antioxidant activity, which may be a potentiator and contributor of kidney-related diseases such as chronic kidney disease (CKD), and DN. The main antioxidant enzymes are superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR). SOD1 in the intermembrane space and SOD2 is released to the matrix. Levels of H₂O₂ are reduced to water through the cooperation between the antioxidant enzymes schematically represented in the scheme.