Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD) worldwide. A significant number of drugs have been clinically investigated for the treatment of DKD. However, a large proportion of patients still develop end-stage kidney disease unstoppably. As a result, new effective therapies are urgently needed to slow down the progression of DKD. Recently, there is increasing evidence that targeted drug delivery strategies such as large molecule carriers, small molecule prodrugs, and nanoparticles can improve drug efficacy and reduce adverse side effects. There is no doubt that targeted drug delivery strategies have epoch-making significance and great application prospects for the treatment of DKD. In addition, the proximal tubule plays a very critical role in the progression of DKD. Consequently, the purpose of this paper is to summarize the current understanding of proximal tubule cell-targeted therapy, screen for optimal targeting strategies, and find new therapeutic approaches for the treatment of DKD.
Diabetic kidney disease (DKD) is the predominant complication of diabetes mellitus (DM) and the leading cause of chronic kidney disease and end-stage renal disease worldwide, which are major risk factors for death. The pathogenesis of DKD is very complicated, including inflammation, autophagy impairment, oxidative stress, and so on. Recently, accumulating evidence suggests that the loss of mitochondrial quality control exerts critical roles in the progression of DKD. Mitochondria are essential for eukaryotic cell viability but are extremely vulnerable to damage. The mechanisms of mitochondrial quality control act at the molecular level and the organelle level, including mitochondrial dynamics (fusion and fission), mitophagy, mitochondrial biogenesis, and mitochondrial protein quality control. In this review, we summarize current knowledge of the role of disturbances in mitochondrial quality control in the pathogenesis of DKD and provide potential insights to explore how to delay the onset and development of DKD.
BackgroundAcute kidney injury (AKI), when occurring in diabetic kidney disease (DKD), is known to be more severe and difficult to recover from. Inflammation and apoptosis may contribute to the heightened sensitivity of, and non-recovery from, AKI in patients with DKD. Resolvin D1 (RvD1) is a potent lipid mediator which can inhibit the inflammatory response and apoptosis in many diseases. However, it has been reported that the RvD1 levels were decreased in diabetes, which may explain why DKD is more susceptible to AKI.MethodsFor animal experiments, diabetic nephropathy (DN) mice were induced by streptozotocin (STZ) injection intraperitoneally. Renal ischemia–reperfusion was used to induce AKI. Blood urea nitrogen (BUN) and serum creatinine were determined using commercial kits to indicate renal function. Renal apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Real-time polymerase chain reaction (PCR) was used to detect the marker of inflammatory response. Western blot was used to detect the expression of nuclear factor-κB (NF-κB)-related proteins. For clinical study, 12 cases diagnosed with DKD were enrolled in this study, and an equal number of non-diabetic renal disease patients (NDKD) were recruited as a control group. The serum RvD1 in DKD or NDKD patients were detected through an ELISA kit.ResultsIn clinical study, we found that the serum RvD1 levels were decreased in DKD patients compared to those in NDKD patients. Decreased serum RvD1 levels were responsible for the susceptibility to ischemic AKI in DKD patients. In animal experiments, both the serum RvD1 and renal ALX levels were downregulated. RvD1 treatment could ameliorate renal function and histological damage after ischemic injury in DN mice. RvD1 treatment also could inhibit the inflammatory response. Di-tert-butyl dicarbonate (BOC-2) treatment could deteriorate renal function and histological damage after ischemic injury in non-diabetic mice. RvD1 could inhibit the NF-κB activation and suppress inflammatory response mainly by inhibiting NF-κB signaling.ConclusionRvD1 attenuated susceptibility to ischemic AKI in diabetes by downregulating NF-κB signaling and inhibiting apoptosis. Downregulated serum RvD1 levels could be the crucial factor for susceptibility to ischemic AKI in diabetes.
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