Curcumin activates the p38MPAK-HSP25 pathway in vitro but fails to attenuate diabetic nephropathy in DBA2J mice despite urinary clearance documented by HPLC.

Abstract

BACKGROUND:

Curcumin has anti-inflammatory, anti-oxidant, and anti-proliferative properties, and depending upon the experimental circumstances, may be pro- or anti-apoptotic. Many of these biological actions could ameliorate diabetic nephropathy.

METHODS/DESIGN:

Mouse podocytes, cultured in basal or high glucose conditions, underwent acute exposure to curcumin. Western blots for p38-MAPK, COX-2 and cleaved caspase-3; isoelectric focusing for HSP25 phosphorylation; and DNase I assays for F- to G- actin cleavage were performed for in vitro analyses. In vivo studies examined the effects of dietary curcumin on the development of diabetic nephropathy in streptozotocin (Stz)-induced diabetes in DBA2J mice. Urinary albumin to creatinine ratios were obtained, high performance liquid chromatography was performed for urinary curcuminoid measurements, and Western blots for p38-MAPK and total HSP25 were performed.

RESULTS:

Curcumin enhanced the phosphorylation of both p38MAPK and downstream HSP25; inhibited COX-2; induced a trend towards attenuation of F- to G-actin cleavage; and dramatically inhibited the activation of caspase-3 in vitro. In curcumin-treated DBA2J mice with Stz-diabetes, HPLC measurements confirmed the presence of urinary curcuminoid. Nevertheless, dietary provision of curcumin either before or after the induction of diabetes failed to attenuate albuminuria.

CONCLUSIONS:

Apart from species, strain, early differences in glycemic control, and/or dosing effects, the failure to modulate albuminuria may have been due to a decrement in renal HSP25 or stimulation of the 12/15 lipoxygenase pathway in DBA2J mice fed curcumin. In addition, these studies suggest that timed urine collections may be useful for monitoring curcumin dosing and renal pharmacodynamic effects.

• Authors: Jun Ma, Lynetta Phillips, Ying Wang, Tiane Dai, Janine LaPage, Rama Natarajan, Sharon G Adler
• Journal: BMC complementary and alternative medicine (BMC Complement Altern Med) Vol. 10 Pg. 67 (Nov 12 2010) ISSN: 1472-6882 [Electronic] England
• PMID: 21073732 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Actins
• Anti-Inflammatory Agents
• Antioxidants
• Caspase Inhibitors
• HSP27 Heat-Shock Proteins
• Plant Extracts
• Cyclooxygenase 2
• p38 Mitogen-Activated Protein Kinases
• Curcumin

Topics

• Actins (metabolism)
• Albuminuria (drug therapy)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Antioxidants (pharmacology)
• Caspase Inhibitors
• Chromatography, High Pressure Liquid
• Curcumin (analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Cyclooxygenase 2 (metabolism)
• Diabetic Nephropathies (drug therapy, metabolism)
• Diet
• HSP27 Heat-Shock Proteins (metabolism)
• Kidney (drug effects)
• Male
• Mice
• Mice, Inbred DBA
• Phosphorylation
• Plant Extracts (pharmacology)
• Podocytes (drug effects)
• Signal Transduction (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)