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, 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 /K -ATPase, Na /H exchangers, and Na -HCO3 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. To extend the potential impact of the provocative findings from this study, a critical role of PPAR in water transport may be implicated in cellular functions outside of the kidneys, because AQPs and water transport also play important roles in various physiological and pathological processes in other organ systems, for example, cell proliferation, vascular permeability, neuroexcitation, airway mucus production, inflammation, peripheral and organ edema, ischemic/reperfusion injury, tumorigenesis, etc. (20, 21). It is well known that PPAR participates in a large variety of cellular processes (12, 13, 19), most of which overlap with those involving AQPs and water transport. The interaction between AQPs and PPAR may exist in the mechanisms regulating cell functions or in the development of different diseases. Therefore, regulation of water transport by PPAR may represent a novel mechanism contributing to PPAR mediated effects in different cell types and tissues, not only in the kidneys. Second, whether PPAR -mediated water reabsorption contributes to PPAR agonist-induced fluid retention, and if so, whether targeting water reabsorption can be used as a therapeutic strategy for PPAR -induced fluid retention. PPAR agonists Thiazolidinediones (TZDs) are highly effective in Type 2 diabetes. However, fluid retention is the most important side effect that restricts the clinical use of this class of drugs (2, 6). Although it has been suggested that TZDs induce fluid retention by increasing sodium transport via ENaC in the collecting duct, many studies show contradictory results that do not support such a conclusion (2, 6, 7, 14). The mechanisms mediating TZD-induced fluid retention are apparently multifactorial and remain to be clarified (2, 6, 7, 14). The findings in the study by Zhou et al. (23) provide strong evidence for the possible involvement of water transport in TZD-induced fluid Address for reprint requests and other correspondence: N. Li, Dept. of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth Univ., PO Box 980613, Richmond, VA 23298 (e-mail: [email protected]). Physiol Genomics 47: 538–540, 2015; doi:10.1152/physiolgenomics.00093.2015. Editorial Focus