MiR-21 alleviates renal tubular epithelial cells injury induced by ischemia by targeting TLR4.

Renal ischemia is the initial stage of kidney damage, leading to mitochondrial metabolism disorders and cell necrosis. In this study, we aimed to investigate the biological functions and potential mechanisms of miR-21 in protecting renal tubular epithelial cells from oxidative stress and apoptosis following oxygen glucose deprivation (OGD). Following an OGD injury, miR-21 levels increased in HK-2 renal tubular epithelial cells. Overexpression of miR-21 decreased the protein expressions of cleaved caspase-3, BAX, P53, cell apoptosis and increased Bcl-2 expression in HK-2 cells with OGD injury. In vivo studies found that miR-21 agomir reduced renal tissue apoptosis, while miR-21 antagomir increased it. In addition, overexpression of miR-21 reduced levels of reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) in HK-2 cells with OGD injury. However, miR-21 inhibition exhibited the opposite effect. A dual-luciferase reporter assay demonstrated that miR-21 directly regulates Toll-like receptor 4 (TLR4) by targeting the 3'-UTR of TLR4 mRNA. Overexpression of miR-21 led to decreased TLR4 protein expression, and TLR4 knockdown was shown to greatly increase AKT activity in HK-2 cells by in vitro kinase assay. Additionally, TLR4 knockdown promoted AKT phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression, while TLR4 overexpression inhibited these processes. Furthermore, AKT activation abolished the effect of TLR4 on HIF-1α, while AKT inhibition decreased the expression of TLR4 on HIF-1α in TLR4 knockdown HK-2 cells. Further study revealed that HIF-1α inhibition abolished the protective effect of miR-21 overexpression on ROS, LDH levels and cell apoptosis in HK-2 cells after OGD injury, which is indicated by increased levels of ROS and LDH, as well as increased cell apoptosis after HIF-1α inhibition in miR-21-treated HK-2 cells. In conclusion, miR-21 defends OGD-induced HK-2 cell injury via the TLR4/AKT/HIF-1α axis.

HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-ß1 through ERK1/2 and JNK MAPK pathways.

Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-ß(1)-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-ß(1)-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-ß(1) would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

Roles of pattern recognition receptors in diabetic nephropathy.

Diabetic nephropathy (DN) is currently the most common complication of diabetes. It is considered to be one of the leading causes of end-stage renal disease (ESRD) and affects many diabetic patients. The pathogenesis of DN is extremely complex and has not yet been clarified; however, in recent years, increasing evidence has shown the important role of innate immunity in DN pathogenesis. Pattern recognition receptors (PRRs) are important components of the innate immune system and have a significant impact on the occurrence and development of DN. In this review, we classify PRRs into secretory, endocytic, and signal transduction PRRs according to the relationship between the PRRs and subcellular compartments. PRRs can recognize related pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), thus triggering a series of inflammatory responses, promoting renal fibrosis, and finally causing renal impairment. In this review, we describe the proposed role of each type of PRRs in the development and progression of DN.

Evidence of altered brain network centrality in patients with diabetic nephropathy and retinopathy: an fMRI study using a voxel-wise degree centrality approach.

BACKGROUND: Over recent years, some researchers believe that diabetic nephropathy (DN) and diabetic retinopathy (DR) both independently increase the incidence of brain diseases, such as stroke, cerebral infarction, and cerebral hemorrhage. In the present study, we used the voxel-wise degree centrality (DC) method to investigate potential changes of functional network brain activity in patients with DN and retinopathy (DNR). METHODS: Twenty DNR patients (9 men, 11 women) and 20 healthy controls (HCs; 9 men, 11 women) were recruited; the controls were matched for age, sex, and educational background. All subjects underwent resting-state functional magnetic resonance imaging. Ophthalmoscopy, renal biopsy and single-photon emission computed tomography were used to evaluate microvascular lesions in the eye and kidney. Data were categorized using receiver operating characteristic curves, and correlation analysis was performed using Pearson's correlation analysis. RESULTS: Compared with HCs, DNR patients showed reduced mean DC values in the right inferior temporal gyrus (RITG) and left subcallosal gyrus regions (LSG) and increased mean DC values in the bilateral precuneus (BP). Moreover, mean DC in the BP was correlated with renal estimated glomerular filtration rate (eGFR; r = 0.762). The area under the curve (AUC) value was 0.829 for BP and 0.839 for RITG and LSG. CONCLUSION: DNR patients showed dysfunction in three different brain regions. The linear correlation between eGFR and mean brain DC values indicates the presence of common diabetic microangiopathy in the brain and kidney, which may provide new ideas for multiorgan microvascular lesions of diabetics.

The predictive potential of altered spontaneous brain activity patterns in diabetic retinopathy and nephropathy.

OBJECTIVE: The amplitude of low-frequency fluctuation (ALFF) fMRI technique was used to study the changes of spontaneous brain activity in patients with diabetic retinopathy and nephropathy (DRN), and to explore the application of ALFF technique in the potential prediction and the targeted prevention of diabetic microangiopathy. METHODS: Nineteen patients with diabetic retinopathy and nephropathy and 19 healthy controls (HCs) were matched for age and gender. Spontaneous cerebral activity variations were investigated using the ALFF technique. The average ALFF values of the DRN patients and the HCs were classified utilizing receiver operating characteristic (ROC) curves. RESULTS: In contrast to the results in the HCs, the patients with DRN had significantly higher ALFF values in the cerebellum (bilaterally in the posterior and anterior lobes) and the left inferior temporal gyrus, but the ALFF values of the bilateral medial frontal gyrus, right superior temporal gyrus, right middle frontal gyrus, left middle/inferior frontal gyrus, bilateral precuneus, and left inferior parietal lobule were lower. ROC curve analysis of each brain region showed the accuracy of AUC was excellent. However, the mean ALFF values in the different regions did not correlate with clinical performance. The subjects showed abnormal neuronal synchronization in many areas of the brain, which is consistent with cognitive and visual functional deficits. CONCLUSION: Abnormal spontaneous activity was detected in many areas of the brain, which may provide useful information for understanding the pathology of DRN. Abnormal ALFF values of these brain regions may be of predictive value in the development of early DRN and be a targeted intervention indicator for individualized treatment of diabetic microvascular diseases.