Chronic kidney disease is associated with higher risk of cardiovascular complication and this interaction can lead to accelerated dysfunction in both organs. Renalase, a kidney‐derived cytokine, not only protects against various renal diseases but also exerts cardio‐protective effects. Here, we investigated the role of renalase in the progression of cardiorenal syndrome (CRS) after subtotal nephrectomy. Sprague–Dawley rats were randomly subjected to sham operation or subtotal (5/6) nephrectomy (STNx). Two weeks after surgery, sham rats were intravenously injected with Hanks' balanced salt solution (sham), and STNx rats were randomly intravenously injected with adenovirus‐β‐gal (STNx+Ad‐β‐gal) or adenovirus‐renalase (STNx+Ad‐renalase) respectively. After 4 weeks of therapy, Ad‐renalase administration significantly restored plasma, kidney and heart renalase expression levels in STNx rats. We noticed that STNx rats receiving Ad‐renalase exhibited reduced proteinuria, glomerular hypertrophy and interstitial fibrosis after renal ablation compared with STNx rats receiving Ad‐β‐gal; these changes were associated with significant decreased expression of genes for fibrosis markers, proinflammatory cytokines and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components. At the same time, systemic delivery of renalase attenuated hypertension, cardiomyocytes hypertrophy and cardiac interstitial fibrosis; prevented cardiac remodelling through inhibition of pro‐fibrotic genes expression and phosphorylation of extracellular signal‐regulated kinase (ERK)‐1/2. In summary, these results indicate that renalase protects against renal injury and cardiac remodelling after subtotal nephrectomy via inhibiting inflammation, oxidative stress and phosphorylation of ERK‐1/2. Renalase shows potential as a therapeutic target for the prevention and treatment of CRS in patients with chronic kidney disease.
Renal fibrosis is the final common pathway of chronic kidney disease (CKD), and no effective medication is available clinically for managing its progression. Metformin was initially developed as an anti-diabetic drug and recently gained attention for its potential in the treatment of other diseases. In this study, we investigated its effects on renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO) in vivo and in angiotensin II (Ang II)–treated renal fibroblast NRK-49F cells in vitro. Our data showed that UUO induced renal fibrosis and combined with the activation of ERK signaling, the upregulation of fibronectin, collagen I, and transforming growth factor-β (TGF-β). The administration of metformin inhibited the activation of ERK signaling and attenuated the production of extracellular matrix (ECM) proteins and collagen deposition in the obstructed kidneys. In cultured renal fibroblasts, Ang II increased the expression of fibronectin and collagen I and also activated ERK signaling and TGF-β in a time-dependent manner. Pretreatment of the cells with metformin blocked Ang II–induced ERK signaling activation and ECM overproduction. Our results show that metformin prevents renal fibrosis, possibly through the inhibition of ERK signaling, and may be a novel strategy for the treatment of renal fibrosis.
Aim: To investigate the effects of ROS scavenger N-acetylcysteine (NAC) on angiotensin II (Ang II)-mediated renal fibrosis in vivo and in vitro. Methods: Mice were subjected to unilateral ureteral obstruction (UUO), and then treated with vehicle or NAC (250 mg/kg, ip) for 7 days. Histological changes of the obstructed kidneys were observed with Masson's trichrome staining. ROS levels were detected with DHE staining. The expression of relevant proteins in the obstructed kidneys was assessed using Western blotting assays. Cultured rat renal fibroblast NRK-49F cells were used for in vitro experiments. Results: In the obstructed kidneys, Ang II levels were significantly elevated, and collagen I was accumulated in the interstitial spaces. Furthermore, ROS production and the expression of p47 (a key subunit of NADPH oxidase complexes) were increased in a timedependent manner; the expression of fibronectin, α-SMA and TGF-β were upregulated. Administration of NAC significantly alleviated the fibrotic responses in the obstructed kidneys. In cultured NRK-49F cells, treatment with Ang II (0.001-10 μmol/L) increased the expression of fibronectin, collagen I, α-SMA and TGF-β in dose-dependent and time-dependent manners. Ang II also increased ROS production and the phosphorylation of Smad3. Pretreatment with NAC (5 μmol/L) blocked Ang II-induced oxidative stress and ECM production in the cells. Conclusion: In mouse obstructed kidneys, the fibrotic responses result from Ang II upregulation can be alleviated by the ROS scavenger N-acetylcysteine.
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