PMID- 15086903
OWN - NLM
STAT- MEDLINE
DCOM- 20041206
LR  - 20181130
IS  - 0085-2538 (Print)
IS  - 0085-2538 (Linking)
VI  - 65
IP  - 5
DP  - 2004 May
TI  - Pioglitazone increases renal tubular cell albumin uptake but limits 
      proinflammatory and fibrotic responses.
PG  - 1647-53
AB  - BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) 
      agonists, which are known to be critical factors in lipid metabolism, have also 
      been reported to reduce proteinuria. The mechanism and its relevance to 
      progressive nephropathy have not been determined. The aims of this study were to 
      assess the direct effects of a PPARgamma agonist on tubular cell albumin uptake, 
      proinflammatory and profibrotic markers of renal pathology, using an opossum 
      kidney model of proximal tubular cells. METHODS: Cells were exposed to 
      pioglitazone (10 micromol/L) in the presence and absence of low-density 
      lipoprotein (LDL) 100 microg/mL +/- exposure to albumin 1 mg/mL. Results were 
      expressed relative to control (5 mmol/L glucose) conditions. RESULTS: 
      Pioglitazone caused a dose-dependent increase in tubular cell albumin uptake (P < 
      0.0001). Despite the increase in albumin reabsorption, no concurrent increase in 
      inflammatory or profibrotic markers were observed. Exposure to LDL increased 
      monocyte chemoattractant protein-1 (MCP-1) (P < 0.05) and transforming growth 
      factor-beta1 (TGF-beta1) (P < 0.05) production, which were reversed in the 
      presence of pioglitazone. LDL induced increases in MCP-1 and TGF-beta1 were 
      independent of nuclear factor-kappaB (NF-kappaB) transcriptional activity. In 
      contrast, tubular exposure to albumin increased tubular protein uptake, in 
      parallel with an increase in MCP-1 (P= 0.05), TGF-beta1 (P < 0.02) and NF-kappaB 
      transcriptional activity (P < 0.05), which were unaffected by concurrent exposure 
      to pioglitazone. CONCLUSION: These findings suggest that dyslipidemia potentiates 
      renal pathology through mechanisms that may be modified by PPARgamma activation 
      independent of NF-kappaB transcriptional activity. In contrast, tubular exposure 
      to protein induces renal damage through NF-kappaB-dependent mechanisms that are 
      unaffected by PPARgamma activation.
FAU - Zafiriou, Stephen
AU  - Zafiriou S
AD  - Department of Medicine, University of Sydney, Kolling Institute of Medical 
      Research, Royal North Shore Hospital, St. Leonards, New South Wales, Australia.
FAU - Stanners, Scott R
AU  - Stanners SR
FAU - Polhill, Tania S
AU  - Polhill TS
FAU - Poronnik, Philip
AU  - Poronnik P
FAU - Pollock, Carol A
AU  - Pollock CA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Albumins)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (PPAR gamma)
RN  - 0 (Thiazolidinediones)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta1)
RN  - X4OV71U42S (Pioglitazone)
SB  - IM
MH  - Albumins/*metabolism
MH  - Animals
MH  - Biological Transport, Active/drug effects
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Chemokine CCL2/biosynthesis
MH  - Fibrosis
MH  - Genes, Reporter
MH  - Inflammation/prevention & control
MH  - Kidney Tubules/*drug effects/*metabolism/pathology
MH  - NF-kappa B/genetics
MH  - Opossums
MH  - PPAR gamma/agonists/metabolism
MH  - Pioglitazone
MH  - Proteinuria/prevention & control
MH  - Thiazolidinediones/*pharmacology
MH  - Transforming Growth Factor beta/biosynthesis
MH  - Transforming Growth Factor beta1
EDAT- 2004/04/17 05:00
MHDA- 2004/12/16 09:00
CRDT- 2004/04/17 05:00
PHST- 2004/04/17 05:00 [pubmed]
PHST- 2004/12/16 09:00 [medline]
PHST- 2004/04/17 05:00 [entrez]
AID - S0085-2538(15)49895-3 [pii]
AID - 10.1111/j.1523-1755.2004.00574.x [doi]
PST - ppublish
SO  - Kidney Int. 2004 May;65(5):1647-53. doi: 10.1111/j.1523-1755.2004.00574.x.