PMID- 36375645 OWN - NLM STAT- MEDLINE DCOM- 20221202 LR - 20221202 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 302 IP - Pt A DP - 2023 Feb 10 TI - Ginsenoside Rg1 attenuates glomerular fibrosis by inhibiting CD36/TRPC6/NFAT2 signaling in type 2 diabetes mellitus mice. PG - 115923 LID - S0378-8741(22)00962-X [pii] LID - 10.1016/j.jep.2022.115923 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginsenoside Rg1 (Rg1) is one of the main active components in Panax ginseng C. A. Meyer (ginseng), which has been widely used to delay senescence or improve health conditions for more than 2000 years. Increasing studies have revealed that Rg1 could regulate cell proliferation and differentiation, as well as anti-inflammatory and anti-apoptotic effects, and might have protective effects on many chronic kidney diseases. AIM OF THE STUDY: Diabetic nephropathy (DN) is one of the most dangerous microvascular complications of diabetes and is the leading cause of end-stage renal disease worldwide. However, the role and mechanism of Rg1 against high-glucose and high-fat-induced glomerular fibrosis in DN are not clear. This study aimed to investigate the protective effect of Rg1 on DN and its possible mechanism. MATERIALS AND METHODS: The type 2 diabetes mellitus (T2DM) mice models were established with a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ). Urine protein and serum biochemical indexes were detected by corresponding kits. The kidney was stained with H&E, PAS, and Masson to observe the pathological morphology, glycogen deposition, and fibrosis. The expression of CD36 and p-PLC in the kidney cortex was detected by IHC. The expressions of FN and COL4 were detected by IF. Western blot and PCR were performed to examine protein and mRNA expressions of kidney fibrosis and TRPC6/NFAT2-related pathways in DN mice. Calcium imaging was used to examine the effect of Rg1 on [Ca(2+)](i) in PA + HG-induced human mesangial cells (HMCs). Visualization of the interaction between Rg1 and CD36 was detected by molecular docking. RESULTS: Rg1 treatment for 8 weeks could prominently decrease urinary protein, serum creatinine, and urea nitrogen and downgrade blood lipid levels and renal lipid accumulation in T2DM mice. The pathological results indicated that Rg1 treatment attenuated renal pathological injury and glomerular fibrosis. The further results demonstrated that Rg1 treatment remarkably decreased the expressions of CD36, TRPC6, p-PLC, CN, NFAT2, TGF-beta, p-Smad2/3, COL4, and FN in renal tissues from T2DM mice. Calcium imaging results found that Rg1 downgraded the base levels of [Ca(2+)](i) and DeltaRatioF340/F380 after BAPTA and CaCl(2) treatment. Molecular docking results showed that Rg1 could interact with CD36 with a good affinity. CONCLUSION: These results revealed that Rg1 could ameliorate renal lipid accumulation, pathological damage, and glomerular fibrosis in T2DM mice. The mechanism may be involved in reducing the overexpression of CD36 and inhibiting the TRPC6/NFAT2 signaling pathway in renal tissues of T2DM mice. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Han, Yuli AU - Han Y AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Su, Yong AU - Su Y AD - Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China. FAU - Han, Min AU - Han M AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Liu, Yan AU - Liu Y AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Shi, Qifeng AU - Shi Q AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Li, Xuewang AU - Li X AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Wang, Penghui AU - Wang P AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Li, Weiping AU - Li W AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. FAU - Li, Weizu AU - Li W AD - Department of Pharmacology, Basic Medicine College, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, PR China. Electronic address: liweizu@126.com. LA - eng PT - Journal Article DEP - 20221112 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - SY7Q814VUP (Calcium) RN - 0 (CD36 Antigens) RN - PJ788634QY (ginsenoside Rg1) RN - 0 (TRPC6 Cation Channel) RN - 0 (Trpc6 protein, mouse) RN - 0 (Nfatc1 protein, mouse) SB - IM MH - Animals MH - Humans MH - Mice MH - Calcium/metabolism MH - CD36 Antigens/metabolism MH - *Diabetes Mellitus, Type 2/metabolism MH - *Diabetic Nephropathies/pathology MH - Fibrosis MH - Kidney MH - Molecular Docking Simulation MH - Signal Transduction MH - TRPC6 Cation Channel/metabolism OTO - NOTNLM OT - Diabetic nephropathy OT - Ginsenoside Rg1 OT - Glomerular fibrosis OT - TRPC6/NFAT2 signaling OT - Type 2 diabetes mellitus COIS- Declaration of competing interest The authors declare that there are no competing financial interests in this paper. EDAT- 2022/11/15 06:00 MHDA- 2022/12/02 06:00 CRDT- 2022/11/14 19:25 PHST- 2022/09/28 00:00 [received] PHST- 2022/10/27 00:00 [revised] PHST- 2022/11/08 00:00 [accepted] PHST- 2022/11/15 06:00 [pubmed] PHST- 2022/12/02 06:00 [medline] PHST- 2022/11/14 19:25 [entrez] AID - S0378-8741(22)00962-X [pii] AID - 10.1016/j.jep.2022.115923 [doi] PST - ppublish SO - J Ethnopharmacol. 2023 Feb 10;302(Pt A):115923. doi: 10.1016/j.jep.2022.115923. Epub 2022 Nov 12.