Amelioration of neuropilin-1 and RAGE/matrix metalloproteinase-2 pathway-induced renal injury in diabetic rats by rosuvastatin


  • Rabia Nabi IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P., India
  • Sahir Sultan Alvi IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P., India
  • Sultan Alouffi Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Saudi Arabia
  • Saif Khan Department of Basic Dental Sciences, College of Dental Sciences, University of Hail, Hail, Kingdom of Saudi Arabia
  • Adnan Ahmad IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P., India
  • Mahvish Khan Department of Biology, College of Science, University of Hail, Hail, Kingdom of Saudi Arabia
  • Saheem Ahmad Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Saudi Arabia
  • M. Salman Khan IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, 226026, U.P., India



rosuvastatin, neuropilin-1, AGE/RAGE-signaling, carboxymethyl-lysine, fluorogenic AGEs


Paper description:

  • Alleviation of renal injury by rosuvastatin in streptozotocin-induced diabetes in rats was examined.
  • Rosuvastatin administration ameliorated plasma carboxymethyl-lysine (CML) and the renal fluorescent-advanced glycation end-product (AGE)
  • Transcription of RAGE, NFκB-2, TGF-β1 and MMP-2 was suppressed; the circulatory carbonyl content and paraoxonase-1 activity was ameliorated; renal histopathological features were attenuated, evidenced by improved glomerular appearance, Bowman’s space and abundant podocytes.
  • The presented mechanistic insight into the role of rosuvastatin in attenuating diabetes-mediated renal dysfunction shows that rosuvastatin prevented AGE-induced renal injury via stimulation of neuropilin-1 expression and AGE-receptor (RAGE)/matrix metalloproteinase-2 signaling.

Abstract: Advanced glycation end-products (AGEs) induce the production of reactive oxygen species (ROS) and extra cellular matrix (ECM) degradation via suppression of neuropilin-1 (NRP-1) and interaction with AGE-receptors (RAGE). This study aimed to reveal whether modulation of NRP-1 by rosuvastatin (RT) prevents AGE-induced renal injury via targeting RAGE/matrix metalloproteinase-2 (MMP-2) signaling in diabetic rats. Treatment with RT ameliorated the altered level of markers of glycemic control, renal injury, cholesterol, triglyceride (TG) and hepatic HMG-CoA reductase activity; the level of circulatory carboxymethyl-lysine (CML) and the accumulation of fluorogenic-AGEs in renal tissue was reduced; the expression of renal NRP-1, a checkpoint target, was stimulated; the transcription of RAGE, NFκB-2, TGF-β1 and MMP-2 was suppressed; the circulatory carbonyl content (CC) and paraoxonase-1 (PON-1) activity was ameliorated, and renal histopathological features were attenuated as evidenced by improved glomerular appearance, Bowman’s space and abundant podocytes in kidneys. In conclusion, RT exhibited the potential to counteract diabetes and AGE-induced renal pathologies via stimulation of NRP-1, suppression of RAGE, and of genes responsible for ECM disintegration (MMP-2) and the inflammatory response (NFκB-2).


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Nabi R, Alvi SS, Saeed M, Ahmad S, Khan MS. Glycation and HMG-CoA Reductase Inhibitors: Implication in Diabetes and Associated Complications. Curr Diabetes Rev. 2019;15(3):213-23.

Sulaiman MK. Diabetic nephropathy: Recent advances in pathophysiology and challenges in dietary management. Diabetol Metab Syndr. 2019;11:7. doi: 10.1186/s13098-019-0403-4.

Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-45.

Lim AKH. Diabetic nephropathy - Complications and treatment. Int J Nephrol Renovasc Dis. 2014;7:361-81.

Umanath K, Lewis JB. Update on Diabetic Nephropathy: Core Curriculum 2018. Am J Kidney Dis. 2018;71(6):884-95.

Busch M, Franke S, Rüster C, Wolf G. Advanced glycation end-products and the kidney. Eur J Clin Invest. 2010;40(8):742-55.

Nabi R, Alvi SS, Shah A, Chaturvedi CP, Iqbal D, Ahmad S, Khan MS. Modulatory role of HMG-CoA reductase inhibitors and ezetimibe on LDL-AGEs-induced ROS generation and RAGE-associated signalling in HEK-293 Cells. Life Sci. 2019;235:116823.

Manigrasso MB, Juranek J, Ramasamy R, Schmidt AM. Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol Metab. 2014;25(1):15-22.

Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible formicrovascular complications in diabetes: A"glycoxidation-centric" point of view. Nutr Metab Cardiovasc Dis. 2013;23(10):913-9.

Haddad M, Knani I, Bouzidi H, Berriche O, Hammami M, Kerkeni M. Plasma levels of pentosidine, carboxymethyl-lysine, soluble receptor for advanced glycation end products, and metabolic syndrome: The metformin effect. Dis Markers. 2016;2016:6248264.

Nabi R, Alvi SS, Khan RH, Ahmad S, Ahmad S, Khan MS. Antiglycation study of HMG-R inhibitors and tocotrienol against glycated BSA and LDL: A comparative study. Int J Biol Macromol. 2018;116:983-92.

Zakiyanov O, Kalousová M, Zima T, Tesař V. Matrix metalloproteinases in renal diseases: A critical appraisal. Kidney Blood Press Res. 2019;44(3):298-330.

Loeffler I, Wolf G. Transforming growth factor-β and the progression of renal disease. Nephrol Dial Transplant. 2014;29(Suppl 1):i37-i45.

Zhao L, Zou Y, Liu F. Transforming Growth Factor-Beta1 in Diabetic Kidney Disease. Front Cell Dev Biol. 2020;8:187. doi: 10.3389/fcell.2020.00187.

Nabi R, Alvi SS, Shah A, Chaturvedi CP, Faisal M, Alatar AA, Ahmad S, Khan MS. Ezetimibe attenuates experimental diabetes and renal pathologies via targeting the advanced glycation, oxidative stress and AGE-RAGE signalling in rats. Arch Physiol Biochem. 2021;1-16.

Bondeva T, Wolf G. Role of Neuropilin-1 in Diabetic Nephropathy. J Clin Med. 2015;4(6):1293-311.

Alvi SS, Iqbal D, Ahmad S, Khan MS. Molecular rationale delineating the role of lycopene as a potent HMG-CoA reductase inhibitor: in vitro and in silico study. Nat Prod Res. 2016;30(18):2111-4.

Ahmad P, Alvi SS, Iqbal D, Khan MS. Insights into pharmacological mechanisms of polydatin in targeting risk factors-mediated atherosclerosis. Life Sci. 2020;254:117756.

Alvi SS, Ansari IA, Khan I, Iqbal J, Khan MS. Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia. Free Radic Biol Med. 2017;108:394-403.

Bolton WK, Cattran DC, Williams ME, Adler SG, Appel GB, Cartwright K, Foiles PG, Freedman BI, Raskin P, Ratner RE, Spinowitz BS, Whittier FC, Wuerth JP. Randomized Trial of an Inhibitor of Formation of Advanced Glycation End Products in Diabetic Nephropathy. Am J Nephrol. 2004;24(1):32-40.

Salunkhe VA, Mollet IG, Ofori JK, Malm HA, Esguerra JLS, Reinbothe TM, Stenkula KG, Wendt A, Eliasson L, Vikman J. Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion. EBioMedicine. 2016;10:185-94.

Salunkhe VA, Elvstam O, Eliasson L, Wendt A. Rosuvastatin treatment affects both basal and glucose-induced insulin secretion in INS-1 832/13 cells. PLoS One. 2016;11(3):e0151592.

Akhter F, Alvi SS, Ahmad P, Iqbal D, Alshehri BM, Khan MS. Therapeutic efficacy of Boerhaavia diffusa (Linn.) root methanolic extract in attenuating streptozotocin-induced diabetes, diabetes-linked hyperlipidemia and oxidative-stress in rats. Biomed Res Ther. 2019;6(7):3293-306.

Hashim A, Alvi SS, Ansari IA, Salman Khan M. Phyllanthus virgatus forst extract and it’s partially purified fraction ameliorates oxidative stress and retino-nephropathic architecture in streptozotocin-induced diabetic rats. Pak J Pharm Sci. 2019;32(6):2697-708.

Husain I, Akhtar M, Abdin MZ, Islamuddin M, Shaharyar M, Najmi AK. Rosuvastatin ameliorates cognitive impairment in rats fed with high-salt and cholesterol diet via inhibiting acetylcholinesterase activity and amyloid beta peptide aggregation. Hum Exp Toxicol. 2018;37(4):399-411.

Alvi SS, Ansari IA, Ahmad MK, Iqbal J, Khan MS. Lycopene amends LPS induced oxidative stress and hypertriglyceridemia via modulating PCSK-9 expression and Apo-CIII mediated lipoprotein lipase activity. Biomed Pharmacother. 2017;96:1082-93.

Wieland H, Seidel D. A simple specific method for precipitation of low density lipoproteins. J Lipid Res. 1983;24(7):904-9.

Benzie IFF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal Biochem. 1996;239(1):70-6.

Ayub A, Mackness MI, Arrol S, Mackness B, Patel J, Durrington PN. Serum Paraoxonase After Myocardial Infarction. Arterioscler Thromb Vasc Biol. 1999;19(2):330-5.

Nabi R, Alvi SS, Shah MS, Ahmad S, Faisal M, Alatar AA, Khan MS. A biochemical & biophysical study on in-vitro anti-glycating potential of iridin against D-Ribose modified BSA. Arch Biochem Biophys. 2020;686:108373.

Nakagawa T, Yokozawa T, Terasawa K, Nakanishi K. Therapeutic usefulness of Keishi-bukuryo-gan for diabetic nephropathy. J Pharm Pharmacol. 2003;55(2):219-27.

Sensi M, Pricci F, Pugliese G, De Rossi MG, Petrucci AFG, Cristina A, Morano S, Pozzessere G, Valle E, Andreani D, Di Mario U. Role of advanced glycation end-products (AGE) in late diabetic complications. Diabetes Res Clin Pract. 1995;28(1):9-17.

Wang G, Liu Z, Li M, Li Y, Alvi SS, Ansari IA, Khan MS. Ginkgolide B Mediated Alleviation of Inflammatory Cascades and Altered Lipid Metabolism in HUVECs via Targeting PCSK-9 Expression and Functionality. Biomed Res Int. 2019;2019:7284767.

Alvi SS, Ansari IA, Khan MS. Pleiotropic role of lycopene in protecting various risk factors mediated atherosclerosis. Ann Phytomedicine. 2015;4(1):54-60.

Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001;50(6):537-46.

Yazdanimehr S, Mohammadi MT. Protective effects of rosuvastatin against hyperglycemia-induced oxidative damage in the pancreas of streptozotocin-induced diabetic rats. Physiol Pharmacol. 2018;22(1):19-27.

Serdar MA, Serteser M, Ucal Y, Karpuzoglu HF, Aksungar FB, Coskun A, Kilercik M, Ünsal İ, Özpınar A. An Assessment of HbA1c in Diabetes Mellitus and Pre-diabetes Diagnosis: a Multi-centered Data Mining Study. Appl Biochem Biotechnol. 2020;190(1):44-56.

Dabla PK. Renal function in diabetic nephropathy. World J Diabetes. 2010;1(2):48-56.

Mian AN, Schwartz GJ. Measurement and Estimation of Glomerular Filtration Rate in Children. Adv Chronic Kidney Dis. 2017;24(6):348-56.

Yang H, Song Y, Liang YN, Li R. Quercetin treatment improves renal function and protects the kidney in a rat model of adenine-induced chronic kidney disease. Med Sci Monit. 2018;24:4760-6.

Kiconco R, Rugera SP, Kiwanuka GN. Microalbuminuria and Traditional Serum Biomarkers of Nephropathy among Diabetic Patients at Mbarara Regional Referral Hospital in South Western Uganda. J Diabetes Res. 2019; 2019:3534260.

Motawi TK, Shehata NI, ElNokeety MM, El-Emady YF. Potential serum biomarkers for early detection of diabetic nephropathy. Diabetes Res Clin Pract. 2018;136:150-8.

Obia O, Chuemere AN, Chike CPR, Nyeche S. Effect of supplementation of natural honey on serum albumin and total protein of alloxan induced diabetic Wistar rats. Am J Phytomedicine Clin Ther. 2017;5(3):21.

Vergès B. Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia. 2015;58(5):886-99.

Ahmad P, Alvi SS, Salman Khan M. Functioning of organosulfur compounds from garlic (allium sativum linn) in targeting risk factor-mediated atherosclerosis: A cross talk between alternative and modern medicine. In: Akhtar M, Swamy M, Sinniah U, editors. Natural Bio-active Compounds Vol 1, Production and Applications. Springer Singapore; 2019. p. 561-85.

Meneses MJ, Silvestre R, Sousa-Lima I, Macedo MP. Paraoxonase-1 as a regulator of glucose and lipid homeostasis: Impact on the onset and progression of metabolic disorders. Int J Mol Sci. 2019;20(16):4049.

Jaouad L, Milochevitch C, Khalil A. PON1 paraoxonase activity is reduced during HDL oxidation and is an indicator of HDL antioxidant capacity. Free Radic Res. 2003;37(1):77-83.

Ruiz HH, Ramasamy R, Schmidt AM. Advanced glycation end products: Building on the concept of the “common soil” in metabolic disease. Endocrinology. 2020;161(1):bqz006.

Saulnier PJ, Wheelock KM, Howell S, Weil EJ, Tanamas SK, Knowler WC, Lemley K V., Mauer M, Yee B, Nelson RG, Beisswenger PJ. Advanced glycation end products predict loss of renal function and correlate with lesions of diabetic kidney disease in American indians with type 2 diabetes. Diabetes. 2016;65(12):3744-53.

Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev. 2020;40(4):1200-1219.

Ott C, Jacobs K, Haucke E, Santos AN, Grune T, Simm A. Role of advanced glycation end products in cellular signaling. Redox Biol. 2014;2:411-29.

de Medeiros MC, Frasnelli SCT, Bastos A de S, Orrico SRP, Rossa Junior C. Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: Role of p38 MAPK and NF-KB. J Appl Oral Sci. 2014;22(3):185-93.

López-Hernández FJ, López-Novoa JM. Role of TGF-β in chronic kidney disease: An integration of tubular, glomerular and vascular effects. Cell Tissue Res. 2012;347(1):141-54.

Kim ES, Sohn YW, Moon A. TGF-β-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett. 2007;252(1):147-56.

Alvi SS, Ahmad P, Ishrat M, Iqbal D, Khan MS. Secondary metabolites from rosemary(Rosmarinus officinalis L.): Structure, biochemistry and therapeutic implications against neurodegenerative diseases. In: Swamy M, Akhtar M editoers. Natural Bio-active Compounds Vol 2, Chemistry, Pharmacology and Health Care Practices. Springer Singapore; 2019. p. 1-24.




How to Cite

Nabi R, Alvi SS, Alouffi S, Khan S, Ahmad A, Khan M, Ahmad S, Khan MS. Amelioration of neuropilin-1 and RAGE/matrix metalloproteinase-2 pathway-induced renal injury in diabetic rats by rosuvastatin. Arch Biol Sci [Internet]. 2021Jul.13 [cited 2024May24];73(2):265-78. Available from: