Effect of vitamin D analogues calcitriol and paricalcitol in a rat model of puromycin aminonucleoside-induced nephrotic syndrome

Hamdi Metin; Pelin Ertan; Ahmet KeskinoÄŸlu; Elgin Türköz Uluer; Muhammet Burak Batir; Pembe KeskinoÄŸlu; Damla Akogullari; Fethi Sirri Çam

doi:10.14238/pi62.6.2022.382-9

Hamdi Metin md
Pelin Ertan
Ahmet KeskinoÄŸlu
Elgin Türköz Uluer
Muhammet Burak Batir
Pembe KeskinoÄŸlu
Damla Akogullari
Fethi Sirri Çam

DOI: https://doi.org/10.14238/pi62.6.2022.382-9

Keywords: Nephrotic syndrome, Vit D analogues, paricalcitol, proteinuria, nephrin

Abstract

Background Renoprotective effects of vitamin D analogues have been shown in several experimental and clinical studies, the exact mechanism of the therapeutic effectiveness of these analogues in Nephrotic syndrome remains unclear, and these are relatively few studies on potential treatment roles for vitamin D analogues in nephrotic-range proteinuria. ?ndicate similar efficacy of the vitamin D analogues calcitriol and paricalcitol in time-limited amelioration of proteinuria in nephrotic syndrome, yet suggest the likelihood of mechanisms other than direct upregulation of nephrin and podocin in podocytes underlie the renoprotective effects of vitamin D analogues.

Objective To investigate the effect of vitamin D (Vit D) analogues calcitriol and paricalcitol on urinary protein/creatinine ratio (UPCR) and renal podocin and nephrin expression in a rat model of puromycin aminonucleoside (PAN)-induced nephrotic syndrome (NS).

Methods A total of 28 male Wistar Albino rats were separated into 4 groups (n=7 for each) including CON [control; intraperitoneal (IP) saline injection], PAN (NS + IP saline injection), PAN-C (NS + IP 0.4 µg/kg/day calcitriol injection), and PAN-P (NS + IP 240 ng/kg/day paricalcitol injection). Nephrotic syndrome was induced via intravenous (IV) administration of 10mg/100gr PAN. The UPCR as well as histopathological, immuno-histochemical, and real time PCR analyses of kidney tissue specimens were recorded and analyzed among the 4 groups.

Results Median UPCR (Day 4) was significantly lower in both the PAN-C [1.45 (range 1.20-1.80)] and PAN-P [1.40 (range 1.10-1.80)] groups than in the PAN group [2.15 (range 2.00-2.40)] (P<0.01 for each). The PAN group had significantly higher mean UPCR than the CON group [1.75 (range 1.40-2.00); P<0.05]. No significant difference in UPCR was noted between groups on Day 7. Median podocin mRNA expression was significantly higher in the PAN-P group compared to the PAN group [22.55 (range 22.42-23.02) vs. 22.06 (range 21.81-22.06), respectively; (P<0.01)].

Conclusion Seven-day calcitriol and paricalcitol supplementation in a rat model of PAN-induced nephrotic syndrome had similar efficacy, in terms of temporary amelioration of proteinuria.

References

1. Lewis JB, Nielson EG. Glomerular diseases. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison’s principles of internal medicine. 18th ed. New York, NY: McGraw Hill; 2012. p. 283.
2. Yamauchi K, Takano Y, Kasai A, Hayakawa K, Hiramatsu N, Enomoto N, et al. Screening and identification of substances that regulate nephrin gene expression using engineered reporter podocytes. Kidney Int. 2006;70:892-900. DOI: https://doi.org/10.1038/sj.ki.5001625.
3. Yousefzadeh P, Shapses SA, Wang X. Vitamin D Binding Protein Impact on 25-Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions. Int J Endocrinol. 2014;2014:981581. DOI: https://doi.org/10.1155/2014/981581.
4. Bennett MR, Pordal A, Haffner C, Pleasant L, Ma Q, Devarajan P. Urinary Vitamin D-Binding Protein as a Biomarker of Steroid-Resistant Nephrotic Syndrome. Biomark Insights. 2016;11:1-6. DOI: https://doi.org/10.4137/BMI.S31633.
5. Cátia FC, Janete QS, Benedita SM, Liliana SS, Isabel SS, Roberto RA Jr, et al. Calcitriol Prevents Cardiovascular Repercussions in Puromycin Aminonucleoside-Induced Nephrotic Syndrome. Biomed Res Int. 2018;2018:3609645. DOI: https://doi.org/10.1155/2018/3609645.
6. Mizokuchi M, Kubota M, Tomino Y, Koide H. Possible mechanism of impaired calcium and vitamin D metabolism in nephrotic rats. Kidney Int. 1992 Aug;42:335-40. doi: 10.1038/ki.1992.294.
7. Balint E, Marshall CF, Sprague SM. Effect of the vitamin D analogues paricalcitol and calcitriol on bone mineral in vitro. Am J Kidney Dis. 2000;36:789-96. DOI: https://doi.org/10.1053/ajkd.2000.17667.
8. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int. 2003 Apr;63(4):1483-90. DOI: https://doi.org/10.1046/j.1523-1755.2003.00878.x.
9. Schwarz U, Amann K, Orth SR, Simonaviciene A, Wessels S, Ritz E. Effect of 1,25 (OH)2 vitamin D3 on glomerulosclerosis in subtotally nephrectomized rats. Kidney Int. 1998;53:1696-705. DOI: https://doi.org/10.1046/j.1523-1755.1998.00951.x.
10. Kuhlmann A, Haas CS, Gross ML, Reulbach U, Holzinger M, Schwarz U, et al. 1,25-Dihydroxyvitamin D3 decreases podocyte loss and podocyte hypertrophy in the subtotally nephrectomized rat. Am J Physiol Renal Physiol. 2004;286:F526-33. DOI: https://doi.org/10.1152/ajprenal.00316.2003.
11. Liu LJ, Lv JC, Shi SF, Chen YQ, Zhang H, Wang HY. Oral calcitriol for reduction of proteinuria in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis. 2012;59:67-74. DOI: https://doi.org/10.1053/j.ajkd.2011.09.014.
12. He W, Kang YS, Dai C, Liu Y. Blockade of Wnt/?-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. J Am Soc Nephrol. 2011;22:90-103. DOI: https://doi.org/10.1681/ASN.2009121236.
13. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. 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;376:1543-51. DOI: https://doi.org/10.1016/S0140-6736(10)61032-X.
14. Agarwal R, Acharya M, Tian J, Hippensteel RL, Melnick JZ, Qiu P, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 2005 Dec;68(6):2823-8. DOI: https://doi.org/10.1111/j.1523-1755.2005.00755.x.
15. de Borst MH, Hajhosseiny R, Tamez H, Wenger J, Thadhani R, Goldsmith DJ. Active vitamin D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol. 2013;24:1863-71. DOI: https://doi.org/10.1681/ASN.2013030203.
16. Hamano T. Vitamin D and renal outcome: the fourth outcome of CKD-MBD? Oshima Award Address 2015. Clin Exp Nephrol. 2018;22:249-256. DOI: https://doi.org/10.1007/s10157-017-1517-3.
17. Yang S, Li A, Wang J, Liu J, Han Y, Zhang W, et al. Vitamin D Receptor: A Novel Therapeutic Target for Kidney Diseases. Curr Med Chem. 2018;25:3256-3271. DOI: https://doi.org/10.2174/0929867325666180214122352.
18. Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83:253-307. DOI: https://doi.org/10.1152/physrev.00020.2002.
19. Pätäri-Sampo A, Ihalmo P, Holthöfer H. Molecular basis of the glomerular filtration: nephrin and the emerging protein complex at the podocyte slit diaphragm. Ann Med. 2006;38:483-92. DOI: https://doi.org/10.1080/07853890600978149.
20. Patrakka J, Tryggvason K. Nephrin--a unique structural and signaling protein of the kidney filter. Trends Mol Med. 2007;13:396-403. DOI: https://doi.org/10.1016/j.molmed.2007.06.006.
21. Kelly DJ, Aaltonen P, Cox AJ, Rumble JR, Langham R, Panagiotopoulos S, et al. Expression of the slit-diaphragm protein, nephrin, in experimental diabetic nephropathy: differing effects of anti-proteinuric therapies. Nephrol Dial Transplant. 2002;17:1327-32. DOI: https://doi.org/10.1093/ndt/17.7.1327. PMID: 12105259.
22. Pan QR, Ren YL, Zhu JJ, Hu YJ, Zheng JS, Fan H, et al. Resveratrol increases nephrin and podocin expression and alleviates renal damage in rats fed a high-fat diet. Nutrients. 2014;6:2619-31. DOI: https://doi.org/10.3390/nu6072619.
23. Matsui I, Hamano T, Tomida K, Inoue K, Takabatake Y, Nagasawa Y,et al. Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats. Nephrol Dial Transplant. 2009;24:2354-61. DOI: https://doi.org/10.1093/ndt/gfp117.
24. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, et al. 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;376:1543-51. DOI: https://doi.org/10.1016/S0140-6736(10)61032-X.
25. Dedinska I, Laca L, Miklusica J, Palkoci B, Skalova P, Kantarova D, et al. The role of proteinuria, paricalcitol and vitamin D in the development of post-transplant diabetes mellitus. Bratisl Lek Listy. 2018;119:401-407. DOI: https://doi.org/10.4149/BLL_2018_073.
26. Selewski DT, Chen A, Shatat IF, Pais P, Greenbaum LA, Geier P, et al. Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol. 2016;31:465-72. DOI: https://doi.org/10.1007/s00467-015-3236-x. Epub 2015 Oct 23.
27. Auwerx J, De Keyser L, Bouillon R, De Moor P. Decreased free 1,25-dihydroxycholecalciferol index in patients with the nephrotic syndrome. Nephron. 1986;42:231-5. DOI: https://doi.org/10.1159/000183672.
28. Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int. 2012;82:737-47. DOI: https://doi.org/10.1038/ki.2012.176.
29. Furness PN, Hall LL, Shaw JA, Pringle JH. Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome. Nephrol Dial Transplant. 1999;14:1234-7. DOI: https://doi.org/10.1093/ndt/14.5.1234. PMID: 10344367.
30. Huh W, Kim DJ, Kim MK, Kim YG, Oh HY, Ruotsalainen V, et al. Expression of nephrin in acquired human glomerular disease. Nephrol Dial Transplant. 2002;17:478-84. DOI: https://doi.org/10.1093/ndt/17.3.478.
31. Wang SX, Rastaldi MP, Pätäri A, Ahola H, Heikkilä E, Holthöfer H. Patterns of nephrin and a new proteinuria-associated protein expression in human renal diseases. Kidney Int. 2002;61:141-7. DOI: https://doi.org/10.1046/j.1523-1755.2002.00114.x.
32. Pérez-Gómez MV, Ortiz-Arduán A, Lorenzo-Sellares V. Vitamin D and proteinuria: a critical review of molecular bases and clinical experience. Nefrologia. 2013;33:716-26. English, Spanish. DOI: https://doi.org/10.3265/Nefrologia.pre2013.Apr.12025.
33. Takeuchi S, Hiromura K, Tomioka M, Takahashi S, Sakairi T, Maeshima A, et al. The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol. 2010;116:e3-10. DOI: https://doi.org/10.1159/000314668.
34. Reiser J, Sever S. Podocyte biology and pathogenesis of kidney disease. Annu Rev Med. 2013;64:357-66. DOI: https://doi.org/10.1146/annurev-med-050311-163340.
35. Fukuda H, Hidaka T, Takagi-Akiba M, Ichimura K, Oliva Trejo JA, Sasaki Y, ET AL. Podocin is translocated to cytoplasm in puromycin aminonucleoside nephrosis rats and in poor-prognosis patients with IgA nephropathy. Cell Tissue Res. 2015;360:391-400. DOI: https://doi.org/10.1007/s00441-014-2100-9.
36. Kho MC, Park JH, Han BH, Tan R, Yoon JJ, Kim HY, et al. Plantago asiatica L. Ameliorates Puromycin Aminonucleoside-Induced Nephrotic Syndrome by Suppressing Inflammation and Apoptosis. Nutrients. 2017;9:386. DOI: https://doi.org/10.3390/nu9040386.
37. Sanz AB, Santamaría B, Ruiz-Ortega M, Egido J, Ortiz A. Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol. 2008;19:1634-42. DOI: https://doi.org/10.1681/ASN.2007121336.
38. Wang Y, Harris DC. Macrophages in renal disease. J Am Soc Nephrol. 2011 Jan;22(1):21-7. DOI: https://doi.org/10.1681/ASN.2010030269. PMID: 21209251.
39. Zoja C, Abbate M, Remuzzi G. Progression of renal injury toward interstitial inflammation and glomerular sclerosis is dependent on abnormal protein filtration. Nephrol Dial Transplant. 2015;30:706-12. DOI: https://doi.org/10.1093/ndt/gfu261. Epub 2014 Aug 2. PMID: 25087196.
40. Bertani T, Remuzzi G, Rocchi G, Delaini F, Sacchi G, Falchetti M, et al. Steroids and Adriamycin nephrosis. Appl Pathol. 1984;2:32-8. PMID: 6525317.