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Kidney injury initiates metabolic reprogramming in tubule cells that contributes to the development of chronic kidney disease (CKD). Exercise has been associated with beneficial effects in patients with CKD. Here we show that the induction of a myokine, irisin, improves kidney energy metabolism and prevents kidney damage. In response to kidney injury, mice with muscle-specific PGC-1α overexpression (mPGC-1α) exhibit reduced kidney damage and fibrosis. Metabolomics analysis reveals increased ATP production and improved energy metabolism in injured kidneys from mPGC-1α mice. We identify irisin as a serum factor that mediates these metabolic effects during progressive kidney injury by inhibiting TGF-β type 1 receptor. Irisin depletion from serum blunts the induction of oxygen consumption rate observed in tubule cells treated with mPGC-1α serum. In mice, recombinant irisin administration attenuates kidney damage and fibrosis and improves kidney functions. We suggest that myokine-mediated muscle-kidney crosstalk can suppress metabolic reprograming and fibrogenesis during kidney disease.

Progressive peritoneal fibrosis affects patients receiving peritoneal dialysis (PD) and has no reliable treatment. The mechanisms that initiate and sustain peritoneal fibrosis remain incompletely elucidated. To overcome these problems, we developed a strategy that prevents peritoneal fibrosis by suppressing PD-stimulated mesothelial-to-mesenchymal transition (MMT). We evaluated single-cell transcriptomes of mesothelial cells obtained from normal peritoneal biopsy and effluent from PD-treated patients. In cells undergoing MMT, we found cellular heterogeneity and intermediate transition states associated with up-regulation of enzymes involved in glycolysis. The expression of glycolytic enzymes was correlated with the development of MMT. Using gene expression profiling and metabolomics analyses, we confirmed that PD fluid induces metabolic reprogramming, characterized as hyperglycolysis, in mouse peritoneum. We found that transforming growth factor β1 (TGF-β1) can substitute for PD fluid to stimulate hyperglycolysis, suppressing mitochondrial respiration in mesothelial cells. Blockade of hyperglycolysis with 2-deoxyglucose (2-DG) inhibited TGF-β1–induced profibrotic cellular phenotype and peritoneal fibrosis in mice. We developed a triad of adeno-associated viruses that overexpressed microRNA-26a and microRNA-200a while inhibiting microRNA-21a to target hyperglycolysis and fibrotic signaling. Intraperitoneal injection of the viral triad inhibited the development of peritoneal fibrosis induced by PD fluid in mice. We conclude that hyperglycolysis is responsible for MMT and peritoneal fibrogenesis, and this aberrant metabolic state can be corrected by modulating microRNAs in the peritoneum. These results could provide a therapeutic strategy to combat peritoneal fibrosis.

BackgroundA non-dipper blood pressure (BP) pattern is very common in chronic kidney disease (CKD) patients and affects the progression and development of cardiovascular disease. However, data on the reversed dipper BP pattern on target-organ damage in Chinese CKD patients are lacking.MethodsA total of 540 CKD patients were enrolled. Ambulatory blood pressure monitoring (ABPM), clinical BP, ultrasonographic assessment and other clinical data were collected. Univariate and multivariate analyses were used to ascertain the relationship between ABPM results and clinical parameters.ResultsA total of 21.9% CKD patients had a reversed dipper BP pattern, 42% of patients had a non-dipper BP pattern and 36.1% of patients had a dipper BP pattern. Patients with reversed dipper BP pattern had the worst renal function and most severe cardiovascular damages among these CKD patients (p<0.05). The estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) correlated significantly with the rate of decline of nocturnal BP. A reversed dipper BP pattern was an independent factor affecting kidney damage and left ventricular hypertrophy. Age, lower hemoglobin level, higher 24-h systolic BP from ABPM, and higher serum phosphate levels were independent associated with a reversed dipper BP pattern after multivariate logistic regression analyses.ConclusionThe reversed dipper BP pattern is closely related to severe renal damage and cardiovascular injuries in CKD patients, and special attention should be given to these CKD patients.

Endothelial-to-mesenchymal transition (EndMT) can cause loss of tight junctions, which in glomeruli are associated with albuminuria. Here we evaluated the role of EndMT in the development of albuminuria in diabetic nephropathy (DN). We demonstrated that EndMT occurs in the glomerular endothelium of patients with DN, showing by a decrease in CD31 but an increase in α-SMA expression. In glomeruli of db/db mice, there was an increased ROCK1 expression in the endothelium plus a decreased CD31-positive cells. Cultured glomerular endothelial cells (GEnCs) underwent EndMT when stimulated by 30 mM glucose, and exhibited increased permeability. Meanwhile, they showed a higher ROCK1 expression and activation. Notably, inhibition of ROCK1 largely blocked EndMT and the increase in endothelial permeability under this high-glucose condition. In contrast, overexpression of ROCK1 induced these changes. Consistent alterations were observed in vivo that treating db/db mice with the ROCK1 inhibitor, fasudil, substantially suppressed the expression of α-SMA in the glomerular endothelium, and reduced albuminuria. Thus we conclude that ROCK1 is induced by high glucose and it stimulates EndMT, resulting in increased endothelial permeability. Inhibition of ROCK1 could be a therapeutic strategy for preventing glomerular endothelial dysfunction and albuminuria in developing DN.