Critical role of PPARγ in water balance
PEROXISOME PROLIFERATOR-ACTIVATED receptor (PPAR)-␥ is one of the three PPAR subtypes (PPAR␣, PPAR␤/␦, and PPAR␥) that are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily (7, 12, 13, 19) . Far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named, PPARs control the transcription of large number of genes involved in diverse physiological processes, such as metabolism of glucose and lipids, adipogenesis,
... ids, adipogenesis, insulin sensitivity, immune response, cell growth and differentiation, as well as pathophysiological conditions, such as metabolic syndrome, oxidative stress, inflammation, atherosclerosis and cancer, etc. In line with their diverse functions, PPARs present in a large variety of cell types and tissues, including in the kidneys, and have been shown to participate in the regulation of fluid homeostasis (2, 3, 7, 14, 19) . Among the three PPARs, the role of PPAR␥ in fluid homeostasis has been most extensively investigated. Mostly utilizing the agonist of PPAR␥, studies have demonstrated that activation of PPAR␥ promotes fluid retention by stimulating sodium reabsorption in the kidneys through different mechanisms involving epithelial sodium channels (ENaC), Na ϩ /K ϩ -ATPase, Na ϩ /H ϩ exchangers, and Na ϩ -HCO 3 Ϫ cotransporter, etc. (2, 7, 14) . It is thus well recognized that PPAR␥ modulates renal sodium reabsorption. However, little is known regarding the role of PPAR␥ in the regulation of water balance, in particular, under physiological conditions. A seminal article in this issue of Physiological Genomics by Zhou and coworkers (23) has revealed a critical role of PPAR␥ in renal water reabsorption using PPAR␥ knockout (KO) mice. The present study by Zhou et al. (23) demonstrates that mice with inducible global KO of PPAR␥ developed severe polyuria and reduced urine osmolality, accompanied by polydipsia and hyperphagia; furthermore, restriction of food and water intake did not alter the increase in urine volume and the decrease in urine osmolality and resulted in a dramatic loss of body weight and a significant increase in hematocrit in KO mice, which ruled out the influence of polydipsia and hyperphagia on the changes of urinary excretion in KO mice. There was no change in urinary excretion of sodium, potassium, and chloride, further indicating a defect in water reabsorption in KO mice. These findings suggest an essential role of PPAR␥ in urine concentrating capability. Mechanistically, this study found that there was no difference in urinary AVP excretion between KO and control mice under basal conditions or after water depletion, suggesting that deletion of PPAR␥ induced a nephrogenic diabetes insipidus but not central diabetes insipidus. More interestingly, this study showed that the vasopressin (AVP)/ cAMP/aquaporin (AQP)-2 axis was intact in KO mice, as the total abundance or phosphorylation of AQP2 in the kidney or AVP-induced cAMP production in the inner medullary collecting duct suspensions was not suppressed in KO mice. Despite the functional AVP/cAMP/AQP2 axis in KO mice, both acute and chronic 1-desamino-8-D-arginine vasopressin treatment did correct the defect of urine concentrating capability in KO mice, which indicates that PPAR␥ regulates urine concentrating via AVP/AQP2-independent pathways. Taken together, this study not only unravels a novel function of PPAR␥ in regulating water transport but also uncovers a novel mechanism in urine concentrating associated with PPAR␥ signaling. The findings in the study raise a number of interesting questions. First, whether these results have potential implications in physiological and pathological processes other than renal fluid reabsorption. The authors have suggested that their results support PPAR␥ as a key mediator that integrates the status of energy metabolism with renal excretory function and that a better understanding of this pathway may provide insights into the mechanism of disturbance of fluid metabolism associated with metabolic syndrome, as obesity is associated with increased renal fluid reabsorption.