Roles of DNA damage in renal tubular epithelial cells injury

The prevalence of renal diseases including acute kidney injury (AKI) and chronic kidney disease (CKD) is increasing worldwide. However, the pathogenesis of most renal diseases is still unclear and effective treatments are still lacking. DNA damage and the related DNA damage response (DDR) have been confirmed as common pathogenesis of acute kidney injury and chronic kidney disease. Reactive oxygen species (ROS) induced DNA damage is one of the most common types of DNA damage involved in the pathogenesis of acute kidney injury and chronic kidney disease. In recent years, several developments have been made in the field of DNA damage. Herein, we review the roles and developments of DNA damage and DNA damage response in renal tubular epithelial cell injury in acute kidney injury and chronic kidney disease. In this review, we conclude that focusing on DNA damage and DNA damage response may provide valuable diagnostic biomarkers and treatment strategies for renal diseases including acute kidney injury and chronic kidney disease

PPAR γ

Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)γ and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPARγ activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN

Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice

Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities

Therapy targeted to the NLRP3 inflammasome in chronic kidney disease

Background: The NLRP3 inflammasome is a cytoplasmic polymeric protein complex composed of the cytoplasmic sensor NLRP3, the apoptosis-related spot-like protein ASC, and the inflammatory protease caspase-1. NLRP3 activates and releases IL-1β through classical pathways, and IL-18 mediates inflammation and activates gasdermin-D protein to induce cellular pyroptosis. Numerous studies have also emphasized the non-classical pathway activated by the NLRP3 inflammasome in chronic kidney disease (CKD) and the inflammasome-independent function of NLRP3. Summary: The NLRP3-targeting inflammasome and its associated pathways have thus been widely studied in models of CKD treatment, but no drug that targets NLRP3 has thus far been approved for the treatment of CKD. Key Messages: We herein reviewed the current interventional methods for targeting the NLRP3 inflammasome in various CKD models, analyzed their underlying mechanisms of action, classified and compared them, and discussed the advantages and follow-up directions of various interventional methods. This review therefore provides novel ideas and a reference for the development of targeted NLRP3-inflammasome therapy in CKD

Klotho Contributes to Pravastatin Effect on Suppressing IL-6 Production in Endothelial Cells

Both statins and klotho have been shown to be beneficial in vascular diseases. Interleukin- (IL-) 6 is evidenced as an indicator reflecting the stability of atherosclerotic plaque and involved in the pathogenesis of artery atherosclerosis. However, the relationship between statin, klotho, and IL-6 under an inflammatory environment is unknown. Using primary human umbilical vein endothelial cells (HUVECs), pravastatin dose-dependently induced klotho expression in contrast to remarkable suppression to IL-6 expressions determined by qRT-PCR. Moreover, TNF-α-induced IL-6 was partly but significantly blunted by pravastatin detected by ELISA. To further study the role of klotho in modulating IL-6 expression, endothelial cells with klotho overexpression were treated with TNF-α. Importantly, TNF-α-induced IL-6 production was markedly attenuated in klotho-overexpressed cells. In agreement with in vitro data, a marked reduction of klotho mRNA expression was found in isolated peripheral blood mononuclear cells (PBMCs) from patients with atherosclerosis. Together, these data suggested that pravastatin could suppress IL-6 production via promoting klotho expression in endothelial cells under inflammatory stimuli

A H 2

Accumulating evidence demonstrated that hydrogen sulfide (H2S) is highly involved in inflammation, oxidative stress, and apoptosis and contributes to the pathogenesis of kidney diseases. However, the role of H2S in cisplatin nephrotoxicity is still debatable. Here we investigated the effect of GYY4137, a novel slow-releasing H2S donor, on cisplatin nephrotoxicity in mice. Male C57BL/6 mice were pretreated with GYY4137 for 72 h prior to cisplatin injection. After cisplatin treatment for 72 h, mice developed obvious renal dysfunction and kidney injury as evidenced by elevated blood urea nitrogen (BUN) and histological damage. Consistently, these mice also showed increased proinflammatory cytokines such as TNF-α, IL-6, and IL-1β in circulation and/or kidney tissues. Meanwhile, circulating thiobarbituric aid-reactive substances (TBARS) and renal apoptotic indices including caspase-3, Bak, and Bax were all elevated. However, application of GYY4137 further aggravated renal dysfunction and kidney structural injury in line with promoted inflammation, oxidative stress, and apoptotic response following cisplatin treatment. Taken together, our results suggested that GYY4137 exacerbated cisplatin-induced nephrotoxicity in mice possibly through promoting inflammation, oxidative stress, and apoptotic response

Wnt/β-Catenin Signaling and Congenital Abnormalities of Kidney and Urinary Tract

Background: Precise regulation of cell-cell communication is vital for cell survival and normal function during embryogenesis. The Wnt protein family, a highly conserved and extensively studied group, plays a crucial role in key cell-cell signaling events essential for development and regeneration. Congenital anomalies of the kidney and urinary tract (CAKUT) represent a leading cause of chronic kidney disease in children and young adults, and include a variety of birth abnormalities resulting from disrupted genitourinary tract development during embryonic development. The incidence and progression of CAKUT may be related to the Wnt signal transduction mechanism. Summary: This review provides a comprehensive overview of the classical Wnt signaling pathway’s role in CAKUT, explores related molecular mechanisms and provides new targets and intervention methods for the future treatment of the disease. Key Messages: The Wnt signal is intricately engaged in a variety of differentiation processes throughout kidney development