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Diabetic kidney disease (DKD) is an important diabetic microvascular complication, which has become the main cause of end-stage renal disease (ESRD) all over the world. It is of great significance to find effective therapeutic targets and improve the prognosis of the disease. Traditionally, it is believed that the activation of the renin-angiotensin-aldosterone system (RAAS) is the main reason for the progression of DKD, but with the progress of research, it is known that the production of proteinuria in patients with DKD is also related to podocyte injury and loss. Many studies have shown that mitochondrial dysfunction in podocytes plays an important role in the occurrence and development of DKD, and oxidative stress is also the main pathway and common hub of diabetes to the occurrence and development of microvascular and macrovascular complications. Thus, the occurrence and progression of DKD is correlated with not only the activation of the RAAS, but also the damage of mitochondria, oxidative stress, and inflammatory mediators. Besides, diabetes-related metabolic disorders can also cause abnormalities in mitochondrial dynamics, autophagy and cellular signal transduction, which are intertwined in a complex way. Therefore, in this review, we mainly explore the mechanism and the latest research progress of podocyte mitochondria in DKD and summarize the main signal pathways involved in them. Thus, it provides feasible clinical application and future research suggestions for the prevention and treatment of DKD, which has important practical significance for the later treatment of patients with DKD.

Mechanism of progression of diabetic kidney disease mediated by podocyte mitochondrial injury

Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1

The invention relates to the technical field of gene engineering, and particularly relates to a recombinant virus and application thereof in preparation of a medicine for preventing or treating renalfibrosis. According to the technical scheme, the progress of renal fibrosis is retarded since TGF beta1 is negatively regulated based on a transcriptional factor YY1, a key factor causing reduction ofthe transcriptional level of TGF beta1 and target gene thereof is found out, and a series of recombinant viruses containing an SEQ ID NO.1 sequence, especially the transcriptional factor YY1 overexpressed recombinant virus (AAV-YY1 virus), are provided, which can be used for preparing a medicine for preventing or treating renal fibrosis. Therefore, the target gene sequence, recombinant virus andmedicine provided by the invention have a wide clinical application prospect in the aspect of preventing or treating renal fibrosis.

Gao Pan

Papers

Yin Yang 1 protein ameliorates diabetic nephropathy pathology through transcriptional repression of TGFβ1

Recombinant virus and application thereof in preparation of medicine for preventing or treating renal fibrosis