Inhibition of MTOR Activity in Diabetes Mellitus Reduces Proteinuria but Not Renal Accumulation of Hyaluronan

Overview

Journal Ups J Med Sci

Specialty General Medicine

Date 2015 Jul 16

PMID 26175092

Citations 2

Authors

Sara Stridh

Fredrik Palm

Tomoko Takahashi

Mayumi Ikegami-Kawai

Peter Hansell

Affiliations

Soon will be listed here.

Abstract

Objectives: Accumulation of extracellular matrix (ECM) components is an early sign of diabetic nephropathy. Also the glycosaminoglycan hyaluronan (HA) is elevated in the renal interstitium during experimental diabetes. The mammalian target of rapamycin (mTOR) pathway participates in the signaling of hyperglycemia-induced ECM accumulation in the kidney, but this has not yet been investigated for HA. We hypothesized that interstitial HA accumulation during diabetes may involve mTOR activation.

Methods: Diabetic rats (6 weeks post-streptozotocin (STZ)) were treated with rapamycin to inhibit mTOR or vehicle for 2 additional weeks. Kidney function (glomerular filtration rate, renal blood flow, urine output) and regional renal HA content were thereafter analyzed. The ability of the animals to respond to desmopressin was also tested.

Results: Diabetic animals displayed hyperglycemia, proteinuria, hyperfiltration, renal hypertrophy, increased diuresis with reduced urine osmolality, and reduced weight gain. Cortical and outer medullary HA was elevated in diabetic rats. Urine hyaluronidase activity was almost doubled in diabetic rats compared with controls. The ability to respond to desmopressin was absent in diabetic rats. Renal blood flow and arterial blood pressure were unaffected by the diabetic state. In diabetic rats treated with rapamycin the proteinuria was reduced by 32%, while all other parameters were unaffected.

Conclusion: Regional renal accumulation of the ECM component HA is not sensitive to mTOR inhibition by rapamycin, while proteinuria is reduced in established STZ-induced diabetes. Whether the diabetes-induced renal accumulation of HA occurs through different pathways than other ECM components, or is irreversible after being established, remains to be shown.

Citing Articles

Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential.

Yang D, Livingston M, Liu Z, Dong G, Zhang M, Chen J Cell Mol Life Sci. 2017; 75(4):669-688.

PMID: 28871310 PMC: 5771948. DOI: 10.1007/s00018-017-2639-1.

Effects of Rapamycin on Clinical Manifestations and Blood Lipid Parameters in Different Preeclampsia-like Mouse Models.

Yi Y, Yang Z, Han Y, Huai J Chin Med J (Engl). 2017; 130(9):1033-1041.

PMID: 28469097 PMC: 5421172. DOI: 10.4103/0366-6999.204924.

References

Stridh S, Kerjaschki D, Chen Y, Rugheimer L, Astrand A, Johnsson C . Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1. Matrix Biol. 2010; 30(1):62-9. DOI: 10.1016/j.matbio.2010.09.006. View

Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S . Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011; 121(6):2197-209. PMC: 3104746. DOI: 10.1172/JCI44774. View

Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S . mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011; 121(6):2181-96. PMC: 3104745. DOI: 10.1172/JCI44771. View

Mariappan M . Signaling mechanisms in the regulation of renal matrix metabolism in diabetes. Exp Diabetes Res. 2012; 2012:749812. PMC: 3290898. DOI: 10.1155/2012/749812. View

Stridh S, Palm F, Hansell P . Renal interstitial hyaluronan: functional aspects during normal and pathological conditions. Am J Physiol Regul Integr Comp Physiol. 2012; 302(11):R1235-49. DOI: 10.1152/ajpregu.00332.2011. View

Decleves A, Caron N, Voisin V, Legrand A, Bouby N, Kultti A . Synthesis and fragmentation of hyaluronan in renal ischaemia. Nephrol Dial Transplant. 2012; 27(10):3771-81. DOI: 10.1093/ndt/gfs098. View

Brosius 3rd F, Alpers C . New targets for treatment of diabetic nephropathy: what we have learned from animal models. Curr Opin Nephrol Hypertens. 2012; 22(1):17-25. PMC: 3776427. DOI: 10.1097/MNH.0b013e32835b3766. View

Stridh S, Palm F, Hansell P . Inhibition of hyaluronan synthesis in rats reduces renal ability to excrete fluid and electrolytes during acute hydration. Ups J Med Sci. 2013; 118(4):217-21. PMC: 4190891. DOI: 10.3109/03009734.2013.834013. View

Colombaro V, Jadot I, Decleves A, Voisin V, Giordano L, Habsch I . Lack of hyaluronidases exacerbates renal post-ischemic injury, inflammation, and fibrosis. Kidney Int. 2015; 88(1):61-71. DOI: 10.1038/ki.2015.53. View

10.

Kultti A, Karna R, Rilla K, Nurminen P, Koli E, Makkonen K . Methyl-beta-cyclodextrin suppresses hyaluronan synthesis by down-regulation of hyaluronan synthase 2 through inhibition of Akt. J Biol Chem. 2010; 285(30):22901-10. PMC: 2906282. DOI: 10.1074/jbc.M109.088435. View

11.

Gilbert R, Cooper M . The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury?. Kidney Int. 1999; 56(5):1627-37. DOI: 10.1046/j.1523-1755.1999.00721.x. View

12.

Hansell P, Goransson V, Odlind C, Gerdin B, Hallgren R . Hyaluronan content in the kidney in different states of body hydration. Kidney Int. 2000; 58(5):2061-8. DOI: 10.1111/j.1523-1755.2000.00378.x. View

13.

Jones S, Phillips A . Regulation of renal proximal tubular epithelial cell hyaluronan generation: implications for diabetic nephropathy. Kidney Int. 2001; 59(5):1739-49. DOI: 10.1046/j.1523-1755.2001.0590051739.x. View

14.

Bardoux P, Ahloulay M, Le Maout S, Bankir L, Trinh-Trang-Tan M . Aquaporin-2 and urea transporter-A1 are up-regulated in rats with type I diabetes mellitus. Diabetologia. 2001; 44(5):637-45. DOI: 10.1007/s001250051671. View

15.

Takeda M, Babazono T, Nitta K, Iwamoto Y . High glucose stimulates hyaluronan production by renal interstitial fibroblasts through the protein kinase C and transforming growth factor-beta cascade. Metabolism. 2001; 50(7):789-94. DOI: 10.1053/meta.2001.24207. View

16.

Nilsson A, Johnsson C, Friberg P, Hansell P . Renal cortical accumulation of hyaluronan in adult rats exposed neonatally to angiotensin-converting enzyme inhibition. Acta Physiol Scand. 2001; 173(3):343-50. DOI: 10.1046/j.1365-201X.2001.00897.x. View

17.

Goransson V, Johnsson C, Nylander O, Hansell P . Renomedullary and intestinal hyaluronan content during body water excess: a study in rats and gerbils. J Physiol. 2002; 542(Pt 1):315-22. PMC: 2290385. DOI: 10.1113/jphysiol.2001.014894. View

18.

Mason R, Wahab N . Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003; 14(5):1358-73. DOI: 10.1097/01.asn.0000065640.77499.d7. View

19.

Ikegami-Kawai M, Okuda R, Nemoto T, Inada N, Takahashi T . Enhanced activity of serum and urinary hyaluronidases in streptozotocin-induced diabetic Wistar and GK rats. Glycobiology. 2003; 14(1):65-72. DOI: 10.1093/glycob/cwh011. View

20.

Molitch M, DeFronzo R, Franz M, Keane W, Mogensen C, Parving H . Nephropathy in diabetes. Diabetes Care. 2003; 27 Suppl 1:S79-83. DOI: 10.2337/diacare.27.2007.s79. View