title: Inhibition of mTOR activity in diabetes mellitus reduces proteinuria but not renal accumulation of hyaluronan.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a 1 Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Stridh
authors.affiliation: a 1 Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden.|b 2 Department of Medical and Health Sciences, Linköping University , Linköping, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Palm
authors.affiliation: c 3 Faculty of Pharmaceutical Sciences, Hoshi University , Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: c 3 Faculty of Pharmaceutical Sciences, Hoshi University , Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ikegami-Kawai
authors.affiliation: a 1 Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Hansell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000175:diagnosis / Q000188:drug therapy*; D005919:Glomerular Filtration Rate; D006820:Hyaluronic Acid / Q000378:metabolism*; D008297:Male; D011507:Proteinuria / Q000188:drug therapy* / Q000517:prevention & control; D011897:Random Allocation; D051381:Rats; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000008:administration & dosage*; D013311:Streptozocin / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D014563:Urodynamics
chemical_list: D013311:Streptozocin; D006820:Hyaluronic Acid; D003404:Creatinine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Diabetes mellitus; hyaluronan; hyaluronidase; mTOR; nephropathy; rapamycin