Bin Wang1, Honglei Guo2,3, Lilu Ling3, Jialing Ji2, Jianying Niu3, Yong Gu4. 1. Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, China. 2. Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China. 3. Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China. 4. Division of Nephrology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China, yongguvip@163.com.
Abstract
BACKGROUND: Chloroquine (CQ), a classic autophagy inhibitor, is used clinically for malaria prophylaxis and pulmonary hypertension treatment. The adverse effects of CQ on morphological and functional changes in the kidney were investigated in the current study due to CQ accumulation in the kidney. METHODS: Twelve male Sprague-Dawley rats were randomly divided into 2 groups for 4 weeks: group 1, control (n = 6); and group 2, CQ administration group (50 mg-1·kg per day ip; n = 6). Serum aldosterone and vasopressin were measured by radioimmunoassay. Immunofluorescence was used to colocalize Tunel with aquaporin 1, aquaporin 2 (AQP2), and Tamm-Horsfall protein. Expression of AQP2 and mineralocorticoid (MR) was detected by western blot and immunohistochemistry. RESULTS: In the present study, 4 weeks of CQ administration were shown to induce severe kidney injury, including glomerular sclerosis and tubular cells apoptosis, especially distal tubular cells. Decreased expression of LC3II/I and p-AKT was demonstrated in CQ-treated rats. Glomerular and proximal tubule injury were associated with impaired autophagy flux, and distal tubule injury may be associated with downregulated cyclic adenosine monophosphate (cAMP)/PKA/AKT signaling. Both MR and AQP2, which are mainly located in the distal tubule and collecting duct, were significantly reduced in CQ-treated rats, thus leading to increased exosomal secretion of AQP2 in urine. Additionally, chronic CQ administration increased aldosterone and vasopressin levels in serum, but lowered the blood pressure, glomerular filtration rate, and urine concentration. CONCLUSIONS: CQ administration damages glomerular, proximal tubule autophagy, and severe distal tubular cells apoptosis by inhibiting cAMP/PKA/AKT signaling.
BACKGROUND:Chloroquine (CQ), a classic autophagy inhibitor, is used clinically for malaria prophylaxis and pulmonary hypertension treatment. The adverse effects of CQ on morphological and functional changes in the kidney were investigated in the current study due to CQ accumulation in the kidney. METHODS: Twelve male Sprague-Dawley rats were randomly divided into 2 groups for 4 weeks: group 1, control (n = 6); and group 2, CQ administration group (50 mg-1·kg per day ip; n = 6). Serum aldosterone and vasopressin were measured by radioimmunoassay. Immunofluorescence was used to colocalize Tunel with aquaporin 1, aquaporin 2 (AQP2), and Tamm-Horsfall protein. Expression of AQP2 and mineralocorticoid (MR) was detected by western blot and immunohistochemistry. RESULTS: In the present study, 4 weeks of CQ administration were shown to induce severe kidney injury, including glomerular sclerosis and tubular cells apoptosis, especially distal tubular cells. Decreased expression of LC3II/I and p-AKT was demonstrated in CQ-treated rats. Glomerular and proximaltubule injury were associated with impaired autophagy flux, and distal tubule injury may be associated with downregulated cyclic adenosine monophosphate (cAMP)/PKA/AKT signaling. Both MR and AQP2, which are mainly located in the distal tubule and collecting duct, were significantly reduced in CQ-treated rats, thus leading to increased exosomal secretion of AQP2 in urine. Additionally, chronic CQ administration increased aldosterone and vasopressin levels in serum, but lowered the blood pressure, glomerular filtration rate, and urine concentration. CONCLUSIONS:CQ administration damages glomerular, proximal tubule autophagy, and severe distal tubular cells apoptosis by inhibiting cAMP/PKA/AKT signaling.
Authors: H Rahimi; A Allahyari; S Ataei Azimi; M Kamandi; Z Mozaheb; F Zemorshidi; M Khadem-Rezaiyan; A Bary; M Seddigh-Shamsi; M Moeini Nodeh Journal: Trials Date: 2021-05-19 Impact factor: 2.279