Abstract
Purpose
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and sleeve gastrectomy (SG) is considered to be an effective strategy to improve pre-existing DN. However, the mechanism remains unknown.
Materials and Methods
Animal model of DN was induced by high-fat diet (HFD) and streptozotocin (STZ). SG or sham surgery was performed and rats were sacrificed at 4, 8, and 12 weeks after surgery. The basic parameters (blood glucose, body weight, kidney weight), indicators of renal function including serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin, urine creatinine (Ucr), microalbumin creatinine ratio (UACR), ultrastructural changes of glomerulus, and the expression of nephrin gene and protein in glomerular podocytes were compared among groups.
Results
Blood glucose and body weight of SG rats were significantly lower than those of the sham-operated rats, and renal function of SG groups were also significantly improved within the postoperative period of 12 weeks. The results of periodic acid-Schiff staining (PAS) and transmission electron microscopy (TEM) showed that glomerular hypertrophy and accumulation of extracellular matrix proteins were significantly alleviated after SG, and the thickness of basement membrane and the fusion or effacement of foot processes were also significantly improved. The mRNA and protein expression of nephrin in SG groups was significantly higher than that in the sham group.
Conclusion
These results suggest that SG attenuates DN by upregulating the expression of nephrin and improving the ultrastructure of glomerular filtration membrane. This study indicates that SG can be used as an available therapeutic intervention for DN.
Similar content being viewed by others
Data Availability
Research data of current study is available at Xiong, Yacheng (2020), “Sleeve gastrectomy attenuates diabetic nephropathy by upregulating nephrin expressions in diabetic fatty rats,” Mendeley Data, v1 https://doi.org/10.17632/c3d6sg9c69.1.
References
Calcutt NA, Cooper ME, Kern TS, et al. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov. 2009;8(5):417–29. Epub 2009/05/01. eng
Flyvbjerg A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol. 2017;13(5):311–8. Epub 2017/03/07. eng
Miyata T, Suzuki N, van Ypersele de Strihou C. Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? Kidney Int. 2013;84(4):693–702. Epub 2013/03/15. eng
Angrisani L, Santonicola A, Iovino P, et al. IFSO Worldwide Survey 2016: primary, endoluminal, and revisional procedures. Obes Surg. 2018;28(12):3783–94. Epub 2018/08/20. eng
Mingrone G, Bornstein S, Le Roux CW. Optimisation of follow-up after metabolic surgery. Lancet Diabetes Endocrinol. 2018;6(6):487–99. Epub 2018/02/06. eng
Gloy VL, Briel M, Bhatt DL, et al. Bariatric surgery versus non-surgical treatment for obesity: a systematic review and meta-analysis of randomised controlled trials. BMJ (Clinical research ed). 2013;347:f5934. Pubmed Central PMCID: PMC3806364. Epub 2013/10/24. eng
Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet (London, England). 2015;386(9997):964–73. Epub 2015/09/16. eng
Billeter AT, Scheurlen KM, Probst P, et al. Meta-analysis of metabolic surgery versus medical treatment for microvascular complications in patients with type 2 diabetes mellitus. Br J Surg. 2018;105(3):168–81. Epub 2018/02/07. eng
Brethauer SA, Aminian A, Romero-Talamas H, et al. Can diabetes be surgically cured? Long-term metabolic effects of bariatric surgery in obese patients with type 2 diabetes mellitus. Ann Surg. 2013;258(4):628–36. discussion 36-7. Pubmed Central PMCID: PMC4110959. Epub 2013/09/11. eng
Friedman AN, Wolfe B. Is bariatric surgery an effective treatment for type II diabetic kidney disease? Clin J Am Soc Nephrol. 2016;11(3):528–35. Pubmed Central PMCID: PMC4791822. Epub 2015/10/10. eng
Romagnani P, Lasagni L. Modeling the glomerular filtration barrier: are you kidney-ing me? Cell Stem Cell. 2017;21(1):7–9. Epub 2017/07/08. eng
Schlondorff D, Wyatt CM, Campbell KN. Revisiting the determinants of the glomerular filtration barrier: what goes round must come round. Kidney Int. 2017;92(3):533–6. Epub 2017/08/16. eng
Isermann B, Vinnikov IA, Madhusudhan T, et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 2007;13(11):1349–58. Epub 2007/11/06. eng
Inoki K, Mori H, Wang J, et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–96. Pubmed Central PMCID: PMC3104745. Epub 2011/05/25. eng
Fogo AB. The targeted podocyte. J Clin Invest. 2011;121(6):2142–5. Pubmed Central PMCID: PMC3104780. Epub 2011/05/25. eng
Grahammer F, Schell C, Huber TB. The podocyte slit diaphragm--from a thin grey line to a complex signalling hub. Nat Rev Nephrol. 2013;9(10):587–98. Epub 2013/09/04. eng
Hussain S, Romio L, Saleem M, et al. Nephrin deficiency activates NF-kappaB and promotes glomerular injury. J Am Soc Nephrol. 2009;20(8):1733–43. Pubmed Central PMCID: PMC2723981. Epub 2009/06/06. eng
Huber TB, Hartleben B, Kim J, et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol. 2003;23(14):4917–28. Pubmed Central PMCID: PMC162232. Epub 2003/07/02. eng
Bonnet F, Cooper ME, Kawachi H, et al. Irbesartan normalises the deficiency in glomerular nephrin expression in a model of diabetes and hypertension. Diabetologia. 2001;44(7):874–7. Epub 2001/08/18. eng
Dumont V, Tolvanen TA, Kuusela S, et al. PACSIN2 accelerates nephrin trafficking and is up-regulated in diabetic kidney disease. FASEB J. 2017;31(9):3978–90.
Jim B, Ghanta M, Qipo A, et al. Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. PLoS One. 2012;7(5):e36041. Pubmed Central PMCID: PMC3355157. Epub 2012/05/23. eng
Zhang J, Liu J, Qin X. Advances in early biomarkers of diabetic nephropathy. Rev Assoc Med Bras. 1992;64(1):85–92. Epub 2018/03/22. eng
Zhiqing W, Jing W, Haili X, et al. Renal function is ameliorated in a diabetic nephropathy rat model through a duodenal-jejunal bypass. Diabetes Res Clin Pract. 2014;103(1):26–34. Epub 2014/01/09. eng
Wu D, Cheng YG, Huang X, et al. Downregulation of lncRNA MALAT1 contributes to renal functional improvement after duodenal-jejunal bypass in a diabetic rat model. J Physiol Biochem. 2018;74(3):431–9. Epub 2018/05/22. eng
Tesch GH, Allen TJ. Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology (Carlton). 2007;12(3):261–6. Epub 2007/05/15. eng
Wu Q, Zhang X, Zhong M, et al. Effects of bariatric surgery on serum bile acid composition and conjugation in a diabetic rat model. Obes Surg. 2016;26(10):2384–92. Epub 2016/02/05. eng
Wang M, Wu Q, Xie H, et al. Effects of sleeve gastrectomy on serum 12alpha-hydroxylated bile acids in a diabetic rat model. Obes Surg. 2017;27(11):2912–8. Epub 2017/05/17. eng
Falkevall A, Mehlem A, Palombo I, et al. Reducing VEGF-B signaling ameliorates renal lipotoxicity and protects against diabetic kidney disease. Cell Metab. 2017;25(3):713–26. Epub 2017/02/14. eng
Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351(26):2683–93. Epub 2004/12/24. eng
Li SY, Huang PH, Yang AH, et al. Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and dedifferentiation. Kidney Int. 2014;86(2):358–69. Epub 2014/03/29. eng
Morito N, Yoh K, Ojima M, et al. Overexpression of Mafb in podocytes protects against diabetic nephropathy. J Am Soc Nephrol. 2014;25(11):2546–57. Pubmed Central PMCID: PMC4214526. Epub 2014/04/12. eng
Zelmanovitz T, Gross JL, Oliveira JR, et al. The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy. Diabetes Care. 1997;20(4):516–9. Epub 1997/04/01. eng
Kanwar YS, Sun L, Xie P, et al. A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annu Rev Pathol. 2011;6:395–423. Pubmed Central PMCID: PMC3700379. Epub 2011/01/26. eng
Trohatou O, Tsilibary EF, Charonis A, et al. Vitamin D3 ameliorates podocyte injury through the nephrin signalling pathway. J Cell Mol Med. 2017;21(10):2599–609. Pubmed Central PMCID: PMC5618699. Epub 2017/07/01. eng
Pories WJ, Swanson MS, MacDonald KG, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339–50. discussion 50-2. Pubmed Central PMCID: PMC1234815. Epub 1995/09/01. eng
O'Brien R, Johnson E, Haneuse S, et al. Microvascular outcomes in patients with diabetes after bariatric surgery versus usual care: a matched cohort study. Ann Intern Med. 2018;169(5):300–10. Pubmed Central PMCID: PMC6759803. Epub 2018/08/08. eng
Nair M, le Roux CW, Docherty NG. Mechanisms underpinning remission of albuminuria following bariatric surgery. Curr Opin Endocrinol Diabetes Obes. 2016;23(5):366–72. Epub 2016/09/02. eng
Neff KJ, Elliott JA, Corteville C, et al. Effect of Roux-en-Y gastric bypass and diet-induced weight loss on diabetic kidney disease in the Zucker diabetic fatty rat. Surg Obes Relat Dis. 2017;13(1):21–7.
Wnuk M, Anderegg MA, Graber WA, et al. Neuropilin1 regulates glomerular function and basement membrane composition through pericytes in the mouse kidney. Kidney Int. 2017;91(4):868–79. Epub 2016/12/19. eng
Barbosa J, Steffes MW, Sutherland DE, et al. Effect of glycemic control on early diabetic renal lesions. A 5-year randomized controlled clinical trial of insulin-dependent diabetic kidney transplant recipients. Jama. 1994;272(8):600–6. Epub 1994/08/24. eng
McVerry BA, Fisher C, Hopp A, et al. Production of pseudodiabetic renal glomerular changes in mice after repeated injections of glucosylated proteins. Lancet (London, England). 1980;1(8171):738–40. Epub 1980/04/05. eng
Nair V, Komorowsky CV, Weil EJ, et al. A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int. 2018;93(2):439–49. Pubmed Central PMCID: PMC5794609. Epub 2017/10/22. eng
Fiorina P, Vergani A, Bassi R, et al. Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol. 2014;25(7):1415–29. Pubmed Central PMCID: PMC4073425. Epub 2014/03/29. eng
Wang C, He B, Piao D, et al. Roux-en-Y esophagojejunostomy ameliorates renal function through reduction of renal inflammatory and fibrotic markers in diabetic nephropathy. Obes Surg. 2016;26(7):1402–13. Epub 2015/10/30. eng
Wagner N, Morrison H, Pagnotta S, et al. The podocyte protein nephrin is required for cardiac vessel formation. Hum Mol Genet. 2011;20(11):2182–94. Epub 2011/03/16. eng
Putaala H, Soininen R, Kilpelainen P, et al. The murine nephrin gene is specifically expressed in kidney, brain and pancreas: inactivation of the gene leads to massive proteinuria and neonatal death. Hum Mol Genet. 2001;10(1):1–8. Epub 2001/01/04. eng
Langham RG, Kelly DJ, Cox AJ, et al. Proteinuria and the expression of the podocyte slit diaphragm protein, nephrin, in diabetic nephropathy: effects of angiotensin converting enzyme inhibition. Diabetologia. 2002;45(11):1572–6. Epub 2002/11/19. eng
Li X, Chuang PY, D'Agati VD, et al. Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J Am Soc Nephrol. 2015;26(10):2361–77. Pubmed Central PMCID: PMC4587684. Epub 2015/02/04. eng
Lin CL, Wang FS, Hsu YC, et al. Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes. 2010;59(8):1915–25. Pubmed Central PMCID: PMC2911050. Epub 2010/06/05. eng
Lee EY, Kim GT, Hyun M, et al. Peroxisome proliferator-activated receptor-delta activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes. Nephrol Dial Transplant. 2012;27(11):4069–79. Epub 2012/08/16. eng
Tang SC, Leung JC, Chan LY, et al. Renoprotection by rosiglitazone in accelerated type 2 diabetic nephropathy: role of STAT1 inhibition and nephrin restoration. Am J Nephrol. 2010;32(2):145–55. Epub 2010/07/08. eng
Niewczas MA, Pavkov ME, Skupien J, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med. 2019;25(5):805–13. Pubmed Central PMCID: PMC6508971. Epub 2019/04/24. eng
de Boer IH. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):24–30. Pubmed Central PMCID: PMC3867994. Epub 2013/12/21. eng
Li F, Zhang G, Liang J, et al. Sleeve gastrectomy provides a better control of diabetes by decreasing ghrelin in the diabetic Goto-Kakizaki rats. J Gastrointest Surg. 2009;13(12):2302–8. Epub 2009/09/04. eng
Wang W, Jiang S, Tang X, et al. Sex differences in progression of diabetic nephropathy in OVE26 type 1 diabetic mice. Biochim Biophys Acta Mol Basis Dis. 2020;1866(1):165589.
Mottl AK, Buse JB, Ismail-Beigi F, et al. Long-term effects of intensive glycemic and blood pressure control and fenofibrate use on kidney outcomes. Clin J Am Soc Nephrol. 2018;13(11):1693–702. Pubmed Central PMCID: PMC6237052. Epub 2018/10/27. eng
Fioretto P, Zambon A, Rossato M, et al. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016:S165–71.
Li H, Rong P, Ma X, et al. Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life Sci. 2018;215:113–8.
Shcheglova T, Makker S, Tramontano A. Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy. J Am Soc Nephrol: JASN. 2009;20(5):1012–9.
Sollinger HW, Odorico JS, Becker YT, et al. One thousand simultaneous pancreas-kidney transplants at a single center with 22-year follow-up. Ann Surg. 2009;250(4):618–30.
Funding
This study was supported by the National Natural Science Foundation of China (NSFC, Grant Nos .81370496 and 81873647) and Youth Program of National Natural Science Foundation of China (Grant No. 81600059).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Approval
All applicable institutional and/or national guidelines for the care and use of animals were followed.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Xiong, Y., Zhu, W., Xu, Q. et al. Sleeve Gastrectomy Attenuates Diabetic Nephropathy by Upregulating Nephrin Expressions in Diabetic Obese Rats. OBES SURG 30, 2893–2904 (2020). https://doi.org/10.1007/s11695-020-04611-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11695-020-04611-3