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Effects of the Peroxisomal Proliferator-Activated Receptor- Agonist Pioglitazone on Renal and Hormonal Responses to Salt in Healthy Men

Division of Hypertension and Vascular Medicine, Department of Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Dr. Anne Zanchi, Division of Hypertension and Vascular Medicine, Avenue P. Decker, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. E-mail: azanchidel{at}hotmail.com.

Glitazones are used in the treatment of type 2 diabetes as efficient insulin sensitizers. They can, however, induce peripheral edema through an unknown mechanism in up to 18% of cases. In this double-blind, randomized, placebo-controlled, four-way, cross-over study, we examined the effects of a 6-wk administration of pioglitazone (45 mg daily) or placebo on the blood pressure, hormonal, and renal hemodynamic and tubular responses to a low (LS) and a high (HS) sodium diet in healthy volunteers. Pioglitazone had no effect on the systemic and renal hemodynamic responses to salt, except for an increase in daytime heart rate. Urinary sodium excretion and lithium clearance were lower with pioglitazone, particularly with the LS diet (P < 0.05), suggesting increased sodium reabsorption at the proximal tubule. Pioglitazone significantly increased plasma renin activity with the LS (P = 0.02) and HS (P = 0.03) diets. Similar trends were observed with aldosterone. Atrial natriuretic levels did not change with pioglitazone. Body weight increased with pioglitazone in most subjects. Pioglitazone stimulates plasma renin activity and favors sodium retention and weight gain in healthy volunteers. These effects could contribute to the development of edema in some subjects treated with glitazones.

This work was supported by a grant from the Swiss National Fund (Grant 31-63947.00) (to M.B.) and a grant from the Faculty of Medicine (to A.Z.) to support the development of academic careers for women.

Abbreviations: ALAT, Alanine aminotransferase; ANP, atrial natriuretic peptide; ASAT, aspartate aminotransferase; ERPF, effective renal plasma flow; GFR, glomerular filtration rate; GT, -glutamyl transferase; HOMA-IR, homeostasis model assessment for insulin resistance; HS, high sodium; LS, low sodium; PAH, p-aminohippurate; PPAR, peroxisomal proliferator-activated receptor; PRA, plasma renin activity; QUICKI, quantitative insulin sensitivity check index.

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