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Diet and Disease Alter Phosphoinositide Composition and Metabolism in Murine Polycystic Kidneys^1,2,3,

Harold M. Aukema, Tamio Yamaguchi, Koji Tomobe, Diana J. Philbrick, Robert S. Chapkin^*, Hisahide Takahashi and Bruce J. Holub⁴

Department of Nutritional Sciences, University of Guelph, Guelph, Canada N1G 2W1 ^* Faculty of Nutrition, Molecular and Cell Biology Group, Texas A&M University, College Station, TX 77843-2471 Laboratory Animal Center, Fujita Health University, Toyoake, Japan

Because diet can affect the progression of polycystic kidney disease (PKD) and because renal phosphoinositide metabolism is altered in mice with PKD, the effects of diet and disease on phosphoinositide composition and metabolism were examined in kidneys of mice with PKD. The phosphatidylinositol-phosphate (PIP) to phosphatidylinositol (PI) molar ratio was higher (0.034 ± 0.003 vs. 0.023 ± 0.001, P < 0.01) and the PI-bisphosphate (PIP₂) to PIP molar ratio was lower (0.70 ± 0.08 vs. 1.19 ± 0.10, P < 0.05) in kidneys of mice with PKD [DBA/2FG-pgy (pcy)] compared with normal controls (DBA/2J). When initial incorporation (reflecting synthesis) of [³H]inositol into renal phosphoinositides in mice injected with [³H]inositol was measured, the [³H]PIP to [³H]PI ratio was higher in the diseased kidneys compared with normal kidneys (0.016 ± 0.001 vs. 0.013 ± 0.001, P < 0.05), whereas the [³H]PIP₂ to [³H]PIP ratio was not significantly different. In a study using dietary manipulations that alter the progression of PKD in pcy mice (6 vs. 25% casein and sunflower seed oil vs. fish oil in a 2 x 2 design), animals were injected intraperitoneally with [³H]inositol 5 h before killing. In these animals, the [³H]PIP₂ to [³H]PIP ratio seemed to be the best indicator of disease progression. In addition, kidney weight (as altered by diet) was positively correlated (r = 0.62, P = 0.02) with the level of the [³H]PI-3-P isomer relative to total [³H]PIP in the kidney. These results demonstrate that alterations in dietary protein level and lipid composition can modulate renal phos-phoinositide signal transduction in mice with PKD.

KEY WORDS: • phosphoinositide • dietary protein • polycystic kidney disease • dietary lipid • mice

¹ Presented in part at the Annual Meeting of the Federation of American Societies for Experimental Biology, April 1991, Atlanta, GA. [Aukema, H. M., Philbrick, D. J., Yamaguchi, T., Tomobe, K., Takahashi, H. & Holub, B. J., Phosphoinositide composition and metabolism in murine polycystic kidney disease, FASEB J. 5: A1409 (abs.)].

² Supported by a grant to BJH from the Natural Sciences and Engineering Research Council of Canada. HMA was supported by an Ontario Graduate Scholarship.

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed.

Manuscript received 29 July 1994. Revision accepted 10 November 1994.