New insights into molecular mechanisms of diabetic kidney disease

Abstract

Diabetic kidney disease remains a major microvascular complication of diabetes and the most common cause of chronic kidney failure requiring dialysis in the United States. Medical advances over the past century have substantially improved the management of diabetes mellitus and thereby have increased patient survival. However, current standards of care reduce but do not eliminate the risk of diabetic kidney disease, and further studies are warranted to define new strategies for reducing the risk of diabetic kidney disease. In this review, we highlight some of the novel and established molecular mechanisms that contribute to the development of the disease and its outcomes. In particular, we discuss recent advances in our understanding of the molecular mechanisms implicated in the pathogenesis and progression of diabetic kidney disease, with special emphasis on the mitochondrial oxidative stress and microRNA targets. Additionally, candidate genes associated with susceptibility to diabetic kidney disease and alterations in various cytokines, chemokines, and growth factors are addressed briefly.

Keywords: End-stage renal disease (ESRD); diabetes mellitus; diabetic kidney disease; pathogenesis.

Figure 1

Mitochondrial ROS. The mitochondrial matrix contains the components of the TCA cycle and the β-oxidative pathway, which provide reduced NADH and FADH₂ to the electron transport chain, leading to generation of a proton gradient across the inner mitochondrial membrane. Under high-glucose conditions, pyruvate is shuttled to the mitochondria, where it is oxidized by the TCA cycle to produce 4 molecules of NADH and 1 molecule of FADH₂.

Figure 2

Mitochondrial fission and fusion. (A) Mitochondrial networks visualized with MitoTracker Red (Life Technologies) fluorescent dye to monitor mitochondrial morphology under (left) normal or (right) high-glucose conditions. Mitochondria appear as long, tubular, and sometimes branched structures that spread throughout the cytoplasm. However, under high-glucose conditions, they appear dense, small, and fragmented. (B) Mitochondrial fission is driven by Drp1, which resides primarily in the cytoplasm. Under hyperglycemic conditions, Drp1 is activated and recruited to the mitochondria. Drp1 then forms spirals around mitochondria at fission sites, which promote the constriction of mitochondria.

Figure 3

Assembly and activation of NADPH oxidase. In resting conditions, only heterodimeric NOX-p22phox complex resides in the membrane, whereas the other components of the complex are cytosolic. Activation of the enzyme releases a conformational restriction, which results in association of different components of the complex to the plasma membrane.

Figure 4

miRNA biogenesis and function. Pri-miRNA transcription is regulated by RNA polymerase II (Pol II). Pri-miRNA, typically several kilobases long, is converted into pre-miRNA by the RNAse III processing enzyme complex Drosha/DGCR8. This pre-miRNA is exported into the cytosol by the exportin 5/RanGTP complex. Pre-miRNAs are processed further through Dicer to form mature miRNAs that are loaded into the RNA-induced silencing complex (RISC) to perform their gene regulatory functions.

Figure 5

RhoA/ROCK pathway. Rho GTPases cycle between an inactive (GDP)- and an active (GTP)-bound form.

Figure 6

Regulation of ROCK activation. (A) The catalytic domain of ROCK is located at the amino terminus, followed by a coiled-coil–forming region and a pleckstrin-homology (PH) domain with a cysteine-rich domain (CRD) at the carboxyl terminus. (B) Active Rho binds to the RBD domain of ROCK, resulting in an open conformation and thereby activation of the ROCK.