A Pre-Post Study of Vitamin D Supplement Effects on Urinary Megalin: The Emerging Predictive Role of Megalin in Diabetic Nephropathy Progression

Author(s): Violet Kasabri*, Amal Akour, Nailya Bulatova, Maysa Suyagh, Al Motassem Yousef, Hussein Al Hawari, Sameeha Al Shelleh, Jameel Bzour, Hiba Fahmawi

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 20 , Issue 9 , 2020


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Graphical Abstract:


Abstract:

Introduction: Megalin is a renal proximal tubular protein that reabsorbs vitamin D from glomerular filtrates. Previous studies found significantly higher levels of urinary megalin in chronic microvascular complications of diabetes with associated metabolic derangements. This study aimed at testing the effect of vitamin D supplements on urinary megalin levels in diabetic nephropathy (DN) patients with vitamin D hypovitaminosis.

Methods: Sixty-three participants with vitamin D deficiency and diabetic nephropathy (DN) were enrolled in the pre-post study; urinary megalin levels with various clinical parameters and serum levels of vitamin D3 were measured and compared to the baseline at 3- and 6-month intervals.

Results: Interestingly, a supplementation related increase in serum vitamin D3 levels at 3- and 6- month interventions affected a constellation of ameliorations in the DN progression of clinical and metabolic factors. There was a decrease in ACR with a concomitant decrease in urinary megalin and a decrease in blood pressure, fasting plasma glucose (FPG), and low-density lipoprotein – cholesterol (LDL-C) – but an increase in glomerular filtration rate (GFR). Principally, pellet urinary megalin associated positively (p < 0.05) with vitamin D hypovitaminosis and the albumin-to-creatinine ratio (ACR) but negatively (p < 0.05) with Ca2+ and body mass index (BMI).

Conclusion: Vitamin D supplementation could elucidate underlying pathophysiological mechanisms and a prognostic significance of urinary megalin association with DN, obesity/MetS-related dyslipidemia, and hyperglycemia modification. Megalin is a putative sensitive and precise predictive marker and an emerging therapeutic target of renal anomalies.

Keywords: Diabetes mellitus type 2, megalin, diabetic nephropathy, vitamin D, glomerular filtration rate, albumin-tocreatinine ratio.

[1]
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care, 2017, 40(1), 1-142.
[2]
World Health Organization. Department of Non-communicable Disease Surveillance Geneva, Definition, Diagnosis, and Classification of Diabetes Mellitus and its Complications.. 1999.Available at: http://apps.who.int/iris/bitstream/handle/10665/66040/WHO_NCD_NCS_99.2.pdf?sequence (Accessed on November 1, 2019).
[3]
Gross, J.L.; de Azevedo, M.J.; Silveiro, S.P.; Canani, L.H.; Caramori, M.L.; Zelmanovitz, T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care, 2005, 28(1), 164-176.
[http://dx.doi.org/10.2337/diacare.28.1.164 ] [PMID: 15616252]
[4]
Rheinberger, M.; Böger, C.A. Diabetic nephropathy: new insights into diagnosis, prevention and treatment. Dtsch. Med. Wochenschr., 2014, 139(14), 704-706.
[PMID: 24668430]
[5]
Kaseda, R.; Hosojima, M.; Sato, H.; Saito, A. Role of megalin and cubilin in the metabolism of vitamin D(3). Ther. Apher. Dial., 2011, 15(Suppl. 1), 14-17.
[http://dx.doi.org/10.1111/j.1744-9987.2011.00920.x] [PMID: 21595846]
[6]
(a)Ogasawara, S.; Hosojima, M.; Kaseda, R.; Kabasawa, H.; Yamamoto-Kabasawa, K.; Kurosawa, H.; Sato, H.; Iino, N.; Takeda, T.; Suzuki, Y.; Narita, I.; Yamagata, K.; Tomino, Y.; Gejyo, F.; Hirayama, Y.; Sekine, S.; Saito, A. Significance of urinary full-length and ectodomain forms of megalin in patients with type 2 diabetes. Diabetes Care, 2012, 35(5), 1112-1118.
[http://dx.doi.org/10.2337/dc11-1684 ] [PMID: 22410816]
(b)Akour, A.; Kasabri, V.; Bulatova, N. Urinary megalin in association with progression factors of diabetic nephropathy. BMJ, 2019, 120(7), 537-540.
(c)Toi, N.; Inaba, M.; Ishimura, E.; Tsugawa, N.; Imanishi, Y.; Emoto, M.; Hirayama, Y.; Nakatani, S.; Saito, A.; Yamada, S. Significance of urinary C-megalin excretion in vitamin D metabolism in pre-dialysis CKD patients. Sci. Rep., 2019, 9(1), 2207.
[http://dx.doi.org/10.1038/s41598-019-38613-8] [PMID: 30778159]
(d)Kuwahara, S.; Hosojima, M.; Kaneko, R.; Aoki, H.; Nakano, D.; Sasagawa, T.; Kabasawa, H.; Kaseda, R.; Yasukawa, R.; Ishikawa, T.; Suzuki, A.; Sato, H.; Kageyama, S.; Tanaka, T.; Kitamura, N.; Narita, I.; Komatsu, M.; Nishiyama, A.; Saito, A. Megalin-mediated tubuloglomerular alterations in high-fat diet-induced kidney disease. J. Am. Soc. Nephrol., 2016, 27(7), 1996-2008.
[http://dx.doi.org/10.1681/ASN.2015020190 ] [PMID: 26534923]
[7]
(a)Sharif-Barfeh, Z.; Beigoli, S.; Marouzi, S. Multi-spectroscopic and HPLC studies of the interaction between estradiol and cyclophosphamide with human serum albumin: Binary and ternary systems. J. Solution Chem., 2017, 46(2), 488-504.
[http://dx.doi.org/10.1007/s10953-017-0590-2]
(b)Zolfagharzadeh, M.; Pirouzi, M.; Asoodeh, A.; Saberi, M.R.; Chamani, J. A comparison investigation of DNP-binding effects to HSA and HTF by spectroscopic and molecular modeling techniques. J. Biomol. Struct. Dyn., 2014, 32(12), 1936-1952.
[http://dx.doi.org/10.1080/07391102.2013.843062] [PMID: 24125112]
(c)Sanei, H.; Asoodeh, A.; Hamedakbari-Tusi, S.; Chamani, J. Multi-spectroscopic investigations of aspirin and colchicine interactions with human hemoglobin: binary and ternary systems. J. Solution Chem., 2011, 40(11), 1905-1931.
[http://dx.doi.org/10.1007/s10953-011-9766-3]
(d)Mokaberi, P.; Reyhani, V.; Amiri-Tehranizadeh, Z. New insights into the binding behavior of lomefloxacin and human hemoglobin using biophysical techniques: Binary and ternary approaches. New J. Chem., 2019, 43(21), 8132-8145.
[http://dx.doi.org/10.1039/C9NJ01048C]
(e)Kamshad, M.; Jahanshah Talab, M.; Beigoli, S.; Sharifirad, A.; Chamani, J. Use of spectroscopic and zeta potential techniques to study the interaction between lysozyme and curcumin in the presence of silver nanoparticles at different sizes. J. Biomol. Struct. Dyn., 2019, 37(8), 2030-2040.
[http://dx.doi.org/10.1080/07391102.2018.1475258 ] [PMID: 29757090]
(f)Shakibapour, N.; Dehghani Sani, F.; Beigoli, S.; Sadeghian, H.; Chamani, J. Multi-spectroscopic and molecular modeling studies to reveal the interaction between propyl acridone and calf thymus DNA in the presence of histone H1: Binary and ternary approaches. J. Biomol. Struct. Dyn., 2019, 37(2), 359-371.
[http://dx.doi.org/10.1080/07391102.2018.1427629] [PMID: 29338579]
[8]
Saito, A.; Takeda, T.; Hama, H. Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis. Nephrology , 2005, (10 Suppl), 26-31.
[http://dx.doi.org/10.1111/j.1440-1797.2005.00453.x]
[9]
Storm, T.; Tranebjærg, L.; Frykholm, C. ALTEX, 2018, 35(4), 504-515.
[PMID: 29999169]
[10]
Oyama, Y.; Takeda, T.; Hama, H.; Tanuma, A.; Iino, N.; Sato, K.; Kaseda, R.; Ma, M.; Yamamoto, T.; Fujii, H.; Kazama, J.J.; Odani, S.; Terada, Y.; Mizuta, K.; Gejyo, F.; Saito, A. Evidence for megalin-mediated proximal tubular uptake of L-FABP, a carrier of potentially nephrotoxic molecules. Lab. Invest., 2005, 85(4), 522-531.
[http://dx.doi.org/10.1038/labinvest.3700240 ] [PMID: 15696188]
[11]
Thrailkill, K.M.; Nimmo, T.; Bunn, R.C.; Cockrell, G.E.; Moreau, C.S.; Mackintosh, S.; Edmondson, R.D.; Fowlkes, J.L. Microalbuminuria in type 1 diabetes is associated with enhanced excretion of the endocytic multiligand receptors megalin and cubilin. Diabetes Care, 2009, 32(7), 1266-1268.
[http://dx.doi.org/10.2337/dc09-0112 ] [PMID: 19366958]
[12]
Fowlkes, J.L.; Bunn, R.C.; Cockrell, G.E.; Clark, L.M.; Wahl, E.C.; Lumpkin, C.K.; Thrailkill, K.M. Dysregulation of the intrarenal vitamin D endocytic pathway in a nephropathy-prone mouse model of type 1 diabetes. Exp. Diabetes Res., 2011.2011269378
[http://dx.doi.org/10.1155/2011/269378 ] [PMID: 21747824]
[13]
Saito, A.; Nagai, R.; Tanuma, A.; Hama, H.; Cho, K.; Takeda, T.; Yoshida, Y.; Toda, T.; Shimizu, F.; Horiuchi, S.; Gejyo, F. Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. J. Am. Soc. Nephrol., 2003, 14(5), 1123-1131.
[http://dx.doi.org/10.1097/01.ASN.0000062962.51879.F8] [PMID: 12707383]
[14]
Russo, L.M.; del Re, E.; Brown, D.; Lin, H.Y. Evidence for a role of transforming growth factor (TGF)-beta1 in the induction of postglomerular albuminuria in diabetic nephropathy: amelioration by soluble TGF-beta type II receptor. Diabetes, 2007, 56(2), 380-388.
[http://dx.doi.org/10.2337/db06-1018 ] [PMID: 17259382]
[15]
González, E.A.; Sachdeva, A.; Oliver, D.A.; Martin, K.J. Vitamin D insufficiency and deficiency in chronic kidney disease. A single center observational study. Am. J. Nephrol., 2004, 24(5), 503-510.
[http://dx.doi.org/10.1159/000081023 ] [PMID: 15452403]
[16]
Del Valle, E.; Negri, A.L.; Aguirre, C.; Fradinger, E.; Zanchetta, J.R. Prevalence of 25(OH) vitamin D insufficiency and deficiency in chronic kidney disease stage 5 patients on hemodialysis. Hemodial. Int., 2007, 11(3), 315-321.
[http://dx.doi.org/10.1111/j.1542-4758.2007.00186.x] [PMID: 17576296]
[17]
Diniz, H.F.; Romão, M.F.; Elias, R.M.; Romão Júnior, J.E. Vitamin D deficiency and insufficiency in patients with chronic kidney disease. J. Bras. Nefrol., 2012, 34(1), 58-63.
[http://dx.doi.org/10.1590/S0101-28002012000100009 ] [PMID: 22441183]
[18]
Diaz, V.A.; Mainous, A.G. III; Carek, P.J. III; Wessell, A.M.; Everett, C.J. The association of vitamin D deficiency and insufficiency with diabetic nephropathy: Implications for health disparities. J. Am. Board Fam. Med., 2009, 22(5), 521-527.
[http://dx.doi.org/10.3122/jabfm.2009.05.080231] [PMID: 19734398]
[19]
de Boer, I.H.; Ioannou, G.N.; Kestenbaum, B.; Brunzell, J.D.; Weiss, N.S. 25-Hydroxyvitamin D levels and albuminuria in the Third National Health and Nutrition Examination Survey (NHANES III). Am. J. Kidney Dis., 2007, 50(1), 69-77.
[http://dx.doi.org/10.1053/j.ajkd.2007.04.015] [PMID: 17591526]
[20]
de Zeeuw, D.; Agarwal, R.; Amdahl, M.; Audhya, P.; Coyne, D.; Garimella, T.; Parving, H.H.; Pritchett, Y.; Remuzzi, G.; Ritz, E.; Andress, D. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet, 2010, 376(9752), 1543-1551.
[http://dx.doi.org/10.1016/S0140-6736(10)61032-X ] [PMID: 21055801]
[21]
Alborzi, P.; Patel, N.A.; Peterson, C.; Bills, J.E.; Bekele, D.M.; Bunaye, Z.; Light, R.P.; Agarwal, R. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension, 2008, 52(2), 249-255.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.108.113159 ] [PMID: 18606901]


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Article Details

VOLUME: 20
ISSUE: 9
Year: 2020
Published on: 24 May, 2020
Page: [1552 - 1557]
Pages: 6
DOI: 10.2174/1871530320666200525012811
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