title: Renoprotective effect of pioglitazone by the prevention of glomerular hyperfiltration through the possible restoration of altered macula densa signaling in rats with type 2 diabetic nephropathy.
abstract: OBJECTIVE
  Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy.
  
  
  METHODS
  Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+PGZ).
  
  
  RESULTS
  Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+PGZ rats. Expressions of desmin and TGF-β were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-β expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 ± 2.9% in LET, 64.2 ± 2.7% in OLETF, 87.4 ± 12.1% in OLETF+PGZ; COX-2: 100.8 ± 7.4% in LET, 249.2 ± 19.4% in OLETF, 179.9 ± 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells.
  
  
  CONCLUSIONS
  PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ.
authors.affiliation: Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan.
authors.forename: Juko
authors.initials: J
authors.lastname: Asakura
authors.forename: Hajime
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Kaori
authors.initials: K
authors.lastname: Takayanagi
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Shimazu
authors.forename: Rie
authors.initials: R
authors.lastname: Suge
authors.forename: Taisuke
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Iwashita
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tayama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsuda
authors.forename: Koichi
authors.initials: K
authors.lastname: Kanozawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Araki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitarai
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003893:Desmin / Q000096:biosynthesis; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000517:prevention & control; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000502:physiology*; D007678:Kidney Glomerulus / Q000187:drug effects*; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D020334:Rats, Inbred OLETF; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D003893:Desmin; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000077205:Pioglitazone