title: Distribution of hydrogen sulfide (H₂S)-producing enzymes and the roles of the H₂S donor sodium hydrosulfide in diabetic nephropathy.
abstract: BACKGROUND
  Hydrogen sulfide (H(2)S) has recently been found to play beneficial roles in ameliorating several diseases, including hypertension, atherosclerosis and cardiac/renal ischemia-reperfusion injuries. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), the main enzymes in the transsulfuration pathway, catalyze H(2)S production in mammalian tissues. However, the distributions and precise roles of these enzymes in the kidney have not yet been identified.
  
  
  METHODS
  The present study examined the localization of both enzymes in the normal kidney and the effect of the H(2)S donor sodium hydrosulfide (NaHS) in the renal peritubular capillary (PTC) under conditions of diabetic nephropathy, using pancreatic β-cell-specific calmodulin-overexpressing transgenic mice as a model of diabetes.
  
  
  RESULTS
  In the normal kidney, we detected expression of both CBS and CSE in the brush border and cytoplasm of the proximal tubules, but not in the glomeruli, distal tubules and vascular endothelial cells of renal PTCs. Administration of NaHS increased PTC diameter and blood flow. We further evaluated whether biosynthesis of H(2)S was altered in a spontaneous diabetic model that developed renal lesions similar to human diabetic nephropathy. CSE expression was markedly reduced under diabetic conditions, whereas CBS expression was unaffected. Progressive diabetic nephropathy showed vasoconstriction and a loss of blood flow in PTCs that was ameliorated by NaHS treatment.
  
  
  CONCLUSIONS
  These findings suggest that CSE expression in the proximal tubules may also regulate tubulointerstitial microcirculation via H(2)S production. H(2)S may represent a target of treatment to prevent progression of ischemic injury in diabetic nephropathy.
authors.affiliation: Division of Nephrology, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamamoto
authors.forename: Waichi
authors.initials: W
authors.lastname: Sato
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Tokunori
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kimura
authors.forename: Shigeki
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Enyu
authors.initials: E
authors.lastname: Imai
authors.forename: Seiichi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yuzawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Niki
mesh_terms: D000818:Animals; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000503:physiopathology; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D002147:Calmodulin; D013440:Sulfides; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; D006862:Hydrogen Sulfide