Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Each bar represents the meanSEM of at least 3 independent experiments, with more than 5 mice in each group at each time point. Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence. 2020;32(6):57282. Each bar represents the meanSEM. In the in vitro study, HCQ also suppressed the proliferation of HK-2 cells stimulated by urinary proteins from patients with LN in a dose-dependent manner (Fig. Liu BC, Tang TT, Lv LL, Lan HY. Arthritis Rheumatol. The absorbance at 450nm was measured by a microplate reader (BioTek, ELx800, Winooski, VT, USA). Renal proximal tubular epithelial cells (PTECs), which are mainly involved in reabsorption of filtered proteins and other glomerular filtrates, contain high levels of lysosomes. Tsuruya K, Ninomiya T, Tokumoto M, Hirakawa M, Masutani K, Taniguchi M, et al. J Western blotting analysis of renal KIM-1 in the mice with proteinuric LN subjected to I/R-induced AKI. (Fig.6EH).6EH). IK Western blotting and quantitative analysis of p53 and p21 expression in the HK-2 cells after exposure to HCQ and urinary proteins extracted from patients with LN. Learn why treatments that were developed for malaria are now used for lupus. Examination and scoring of sections were performed by two professional pathologists in a blinded manner. Edelstein CL, Venkatachalam MA, Dong Z. Autophagy inhibition by chloroquine and hydroxychloroquine could adversely affect acute kidney injury and other organ injury in critically ill patients with COVID-19. Yu SM, Bonventre JV. Hydroxychloroquine: a physiologically-based pharmacokinetic model in the context of cancer-related autophagy modulation. B Scr levels in the mice with proteinuric LN administered HCQ for 4weeks. K Quantitative analysis of KIM-1 expression in the mice with proteinuric LN subjected to I/R-induced AKI by Western blotting. Kidney repair after AKI is characterized by restoration of the polarity of PTECs. CAS Kidney Int. *P <0.05, **P <0.01, and ***P <0.001. HCQ impairs the autophagy-lysosomal pathway and accelerates senescence in PTECs. Article 2008;294(6):F126572. EH Western blotting analysis and quantitative analysis of renal p62 in the mice with proteinuric LN subjected to unilateral I/R-induced AKI. Accessibility Original magnification 200. As mentioned above, severe proteinuria is a common clinical manifestation of LN, and excessive inhibition of lysosomes may exacerbate PTEC injury in patients with LN with severe proteinuria. SMAD3 promotes autophagy dysregulation by triggering lysosome depletion in tubular epithelial cells in diabetic nephropathy. G Representative PAS staining images and immunohistochemical staining of renal KIM-1 in the mice with proteinuric LN subjected to I/R-induced AKI. A Representative immunohistochemical staining of renal E-cadherin in the mice with proteinuric LN subjected to I/R-induced AKI. Original magnification 200. Our present data showed that HCQ treatment significantly inhibited renal inflammatory responses. Thus, we inferred that HCQ may act as a double-edged sword in LN with massive proteinuria: HCQ may relieve renal immune inflammatory injuries by inhibiting immune cell lysosomes but may also exacerbate renal injuries by inhibiting lysosomal degradation and disrupting protective autophagy in PTECs. Under conditions involving LN-related massive proteinuria, PTECs display protein overloading due to abundant urinary protein reabsorption, which enhances the degradative burden of PTEC lysosomes. In 1955, the agency approved the antimalarial drug Plaquenil (hydroxychloroquine) which helps to relieve some lupus symptoms such as fatigue, rashes, joint pain or mouth sores. Anti-HAVCR1/TIM1/KIM-1 (kidney injury molecule-1, KIM-1, AF1817) was obtained from R&D Systems (Minneapolis, MN, USA). Human kidney tubular epithelial cells (HK-2) were obtained from the American Type Culture Collection (ATCC, CRL-2190TM) and were as cultured as described previously [19]. wrote the paper. 6IK). Medicine (Baltimore). Hydroxychloroquine (Plaquenil) is a type of antimalarial medicine. 2021;100(4S):S1S276. [50] found that short-term HCQ therapy attenuated I/R-induced AKI, although the autophagy pathway was also inhibited. Blocking the autophagy pathway and accelerating senescence in PTECs by HCQ may reduce cellular resistance to stress. 6AD, HCQ treatment impaired the renal autophagy-lysosomal pathway in the mice with proteinuric LN and induced PTEC senescence, as demonstrated by the accumulation of the autophagy-related protein p62. P<0.05 was defined as significant in this study. L, M Quantitative analysis of glomerular and tubular injury scores of the mice with proteinuric LN. D Quantitative analysis of renal E-cadherin expression in the mice with proteinuric LN subjected to I/R-induced AKI by Western blotting. 2012;82(12):127183. The number of positive cells in ten 400 magnification fields per sample was counted (Olympus, BX64 and DP74, Tokyo, Japan). We found that HCQ induced G1/S arrest and increased the expression of p53 and p21 in PTECs. Ischemic AKI is the serious cause of AKI in both native kidneys and renal allografts. 2018;94(3):634. We detected the expression of the epithelial cell marker E-cadherin, a major component of tubular adherent proteins that maintains intercellular contacts and PTEC polarity in renal tissues. To further confirm the inhibitory effect of HCQ on the autophagy-lysosomal pathway, we incubated HK-2 cells with urinary proteins extracted from patients with LN and treated them with or without HCQ. inability to move the eyes. A Survival rate of the mice with proteinuric LN. Results As expected, HCQ treatment increased the survival ratio and downregulated the levels of serum creatinine in the mice with LN, ameliorated renal lesions, and inhibited renal interstitial inflammation. After administration of HCQ, as shown in Fig. Received 2021 Mar 17; Accepted 2021 Dec 9. N.A., C.Y., Q.P., and H.L. Each bar represents the meanSEM of at least 3 independent experiments, with more than 5 mice in each group at each time point. 6L). Wang X, Bonventre JV, Parrish AR. 2018;24:688291. Each bar represents the meanSEM of at least 3 independent experiments, with more than 5 mice in each group at each time point. This study was approved by the Ethics Committee of Affiliated Hospital of Guangdong Medical University, Zhanjiang, China (No. For lupus nephritis, your dose is 400 mg injected under your skin once per week for 4 weeks. B Quantitative analysis of the SA--gal-positive tubular area. Thus, mice treated with 200mg/kg/day (means 1000mg/kg/day in human) for 1month to explore the potential therapeutic effect of HCQ on proteinuric LN. 2015;308(6):F63949. Moreover, in accordance with the in vivo study, HCQ treatment dose-dependently upregulated the expression of p53 and p21 in HK-2 cells treated with urinary proteins from LN samples (Fig. Dorner T, Furie R. Novel paradigms in systemic lupus erythematosus. Smoothie. 2GK). Ageing Res Rev. Patients with LN, a classical type of CKD, are prone to AKI [14]. For detection of lysosomal degradation, the mean fluorescence intensity of green degradable compounds from DQ-ovalbumin (Invitrogen) in HK-2 cells was analyzed by flow cytometry as described previously [19]. the contents by NLM or the National Institutes of Health. Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence. Accelerated glomerular cell senescence in experimental lupus nephritis. (Fig.1EG),1EG), as well as the renal expression of the proinflammatory cytokines IL-1 and TNF- (Fig. National Library of Medicine (Fig.3H,3H, I). 3J, K). Nair AB, Jacob S. A simple practice guide for dose conversion between animals and human. The primers used in this study included primers for mouse TNF- and IL-1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Alexa 594-conjugated donkey anti-rat IgG (A-21209) was obtained from Thermo Fisher Scientific (Eugene, OR, USA). 1 ). HCQ preadministration suppressed the proliferation of PTECs by arresting cells in G1/S phase and upregulated the expression of cell cycle inhibitors. Unfortunately, a growing body of literature has confirmed that chronic use of HCQ and CQ may induce organ damage [38, 39], including kidney injury [40]. The control LN mice were orally administrated with the same volume of saline during the same time. 2018;93(3):56879. Plaquenil and other anti-malarials are the key to controlling lupus long term, and some lupus patients may be on Plaquenil for the rest of their lives. HCQ promotes PTEC G1/S arrest in the mice with proteinuric LN. Cisplatin, a common chemotherapeutic agent, can induce AKI in rodent with many pathophysiologic features similar to patients. 2020;98(1):2345. G Representative PAS staining images and immunohistochemical staining of renal KIM-1 in the mice with proteinuric LN subjected to I/R-induced AKI. F Quantitative analysis of renal TUNEL staining in the mice with proteinuric LN subjected to I/R-induced AKI. Am J Physiol Renal Physiol. J CCK-8 analysis of the proliferation of HK-2 cells. L Flow cytometric analysis of DQ-ovalbumin staining in HK-2 cells after exposure to HCQ. Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NADPH oxidase. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision), http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Kidney Disease: Improving Global Outcomes, Microtubule-associated protein 1 light chain 3B. Fig.6A,6A, HCQ administration significantly elevated the staining of SA--gal in PTECs. The autoimmunity present in patients with SLE causes local inflammation and tissue damage, and it may present with a variety of symptoms depending on the organ system involved. *P <0.05, **P <0.01, and ***P <0.001. Results: As expected, HCQ treatment increased the survival ratio and downregulated the levels of serum creatinine in the mice with LN, ameliorated renal lesions, and inhibited renal interstitial inflammation. In the present study, we confirmed for the first time that HCQ monotherapy could also preserve renal function and elevate the survival of LN using spontaneous LN models. Increased cellular senescence and vascular rarefaction exacerbate the progression of kidney fibrosis in aged mice following transient ischemic injury. To further confirm the inhibitory effect of HCQ on the autophagy-lysosomal pathway, we incubated HK-2 cells with urinary proteins extracted from patients with LN and treated them with or without HCQ. Update on lupus nephritis. 2011;20(14):155765. All authors read and approved the final paper. Batch CBD Full-Spectrum Gummies. Thus, ischemic- and cisplatin-induced AKI are well accepted models mimicking AKI developed in LN patients. 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