Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and no specific drugs are clinically available. We have previously demonstrated that inhibiting microsomal prostaglandin E synthase-2 (mPGES-2) alleviated type 2 diabetes by enhancing ß cell function and promoting insulin production. However, the involvement of mPGES-2 in DKD remains unclear. Here, we aimed to analyze the association of enhanced mPGES-2 expression with impaired metabolic homeostasis of renal lipids and subsequent renal damage. Notably, global knockout or pharmacological blockage of mPGES-2 attenuated diabetic podocyte injury and tubulointerstitial fibrosis, thereby ameliorating lipid accumulation and lipotoxicity. These findings were further confirmed in podocyte- or tubule-specific mPGES-2-deficient mice. Mechanistically, mPGES-2 and Rev-Erbα competed for heme binding to regulate fatty acid binding protein 5 expression and lipid metabolism in the diabetic kidney. Our findings suggest a potential strategy for treating DKD via mPGES-2 inhibition.

Ganoderic acids alleviate atherosclerosis by inhibiting macrophage M1 polarization via TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND AND AIMS: Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid infiltration and plaque formation in blood vessel walls. Ganoderic acids (GA), a class of major bioactive compounds isolated from the Chinese traditional medicine Ganoderma lucidum, have multiple pharmacological activities. This study aimed to determine the anti-atherosclerotic effect of GA and reveal the pharmacological mechanism. METHODS: ApoE-/- mice were fed a high-cholesterol diet and treated with GA for 16 weeks to induce AS and identify the effect of GA. Network pharmacological analysis was performed to predict the anti-atherosclerotic mechanisms. An invitro cell model was used to explore the effect of GA on macrophage polarization and the possible mechanism involved in bone marrow dereived macrophages (BMDMs) and RAW264.7 cells stimulated with lipopolysaccharide or oxidized low-density lipoprotein. RESULTS: It was found that GA at 5 and 25 mg/kg/d significantly inhibited the development of AS and increased plaque stability, as evidenced by decreased plaque in the aorta, reduced necrotic core size and increased collagen/lipid ratio in lesions. GA reduced the proportion of M1 macrophages in plaques, but had no effect on M2 macrophages. In vitro experiments showed that GA (1, 5, 25 µg/mL) significantly decreased the proportion of CD86+ macrophages and the mRNA levels of IL-6, IL-1ß, and MCP-1 in macrophages. Experimental results showed that GA inhibited M1 macrophage polarization by regulating TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS: This study demonstrated that GA play an important role in plaque stability and macrophage polarization. GA exert the anti-atherosclerotic effect partly by regulating TLR4/MyD88/NF-κB signaling pathways to inhibit M1 polarization of macrophages. Our study provides theoretical basis and experimental data for the pharmacological activity and mechanisms of GA against AS.

Lipin-1 deficiency deteriorates defect of fatty acid ß-oxidation and lipid-related kidney damage in diabetic kidney disease.

Diabetic lipo-toxicity is a fundamental pathophysiologic mechanism in DM and is now increasingly recognized a key determinant of DKD. Targeting lipid metabolic disorders is an important therapeutic strategy for the treatment of DM and its complications, including DKD. This study aimed to explore the molecular mechanism of lipid metabolic regulation in kidney, especially renal PTECs, and elucidate the role of lipid metabolic related molecule lipin-1 in diabetic lipid-related kidney damage. In this study, lipin-1-deficient db/db mouse model and STZ/HFD-induced T2DM mouse model were used to determine the effect of lipin-1 on DKD development. Then RPTCs and LPIN1 knockdown or overexpressed HK-2 cells induced by PA were used to investigate the mechanism. We found that the expression of lipin-1 increased early and then decreased in kidney during the progression of DKD. Glucose and lipid metabolic disorders and renal insufficiency were found in these 2 types of diabetic mouse models. Interestingly, lipin-1 deficiency might be a pathogenic driver of DKD-to-CKD transition, which could further accelerate the imbalance of renal lipid homeostasis, the dysfunction of mitochondrial and energy metabolism in PTECs. Mechanistically, lipin-1 deficiency resulted in aggravated PTECs injury to tubulointerstitial fibrosis in DKD by downregulating FAO via inhibiting PGC-1α/PPARα mediated Cpt1α/HNF4α signaling and upregulating SREBPs to promote fat synthesis. This study provided new insights into the role of lipin-1 as a regulator for maintaining lipid homeostasis in the kidney, especially PTECs, and its deficiency led to the progression of DKD.

Inhibition of intrarenal PRR-RAS pathway by Ganoderma lucidum polysaccharide peptides in proteinuric nephropathy.

Excessive proteinuria leads to renal dysfunction and damage. Ganoderma lucidum polysaccharide peptide (GL-PP) and Ganoderma lucidum polysaccharide peptide 2 (GL-PP2) are biologically active compounds extracted from Ganoderma lucidum. GL-PP has a relative molecular weight of 37,121 with 76.39 % polysaccharides and 16.35 % polypeptides, while GL-PP2 has a relative molecular weight of 31,130, composed of 64.14 % polysaccharides and 17.73 % polypeptides. The xylose: mannose: glucose monosaccharide ratios in GL-PP and GL-PP2 were 4.83:1:7.03 and 2.35:1:9.38, respectively. In this study, we investigated the protective effects of GL-PP and GL-PP2 on proteinuria-induced renal dysfunction and damage using rat and cell models. Both compounds reduced kidney injury, proteinuria, and inhibited the (pro)renin receptor (PRR)-renin-angiotensin system (RAS) pathway, inflammatory cell infiltration, oxidative stress, and fibrosis. GL-PP2 showed stronger inhibition of cyclooxygenase-2 and inducible nitric oxide synthase proteins compared to GL-PP. In cell models, both compounds displayed anti-inflammatory properties and improved cellular viability by inhibiting the PRR-RAS pathway. GL-PP2 has higher feasibility and productivity than GL-PP in pharmacology and industrial production. It shows promise in treating proteinuria-induced renal disease with superior anti-inflammatory effects and economic, safe industrial application prospects. Further research is needed to compare efficacy, mechanisms, clinical applications, and commercial feasibility of GL-PP and GL-PP2.

High urea induces anxiety disorders associated with chronic kidney disease by promoting abnormal proliferation of OPC in amygdala.

Chronic kidney disease (CKD) with anxiety disorder is of a great concern due to its high morbidity and mortality. Urea, as an important toxin in CKD, is not only a pathological factor for complications in patients with CKD, but also is accumulated in the brain of aging and neurodegenerative diseases. However, the pathological role and underlying regulatory mechanism of urea in CKD related mood disorders have not been well established. We previously reported a depression phenotype in mice with abnormal urea metabolism. Since patients with depression are more likely to suffer from anxiety, we speculate that high urea may be an important factor causing anxiety in CKD patients. In adenine-induced CKD mouse model and UT-B-/- mouse model, multiple behavioral studies confirmed that high urea induces anxiety-like behavior. Single-cell transcriptome revealed that down-regulation of Egr1 induced compensatory proliferation of oligodendrocyte progenitor cells (OPC). Myelin-related signaling pathways of oligodendrocytes (OL) were change significant in the urea accumulation amygdala. The study showed that high urea downregulated Egr1 with subsequent upregulation of ERK pathways in OPCs. These data indicate that the pathological role and molecular mechanism of high urea in CKD-related anxiety, and provide objective serological indicator and a potential new drug target for the prevention and treatment of anxiety in CKD patients.

Single hormone or synthetic agonist induces Gs/Gi coupling selectivity of EP receptors via distinct binding modes and propagating paths.

To accomplish concerted physiological reactions, nature has diversified functions of a single hormone at at least two primary levels: 1) Different receptors recognize the same hormone, and 2) different cellular effectors couple to the same hormone-receptor pair [R.P. Xiao, Sci STKE 2001, re15 (2001); L. Hein, J. D. Altman, B.K. Kobilka, Nature 402, 181-184 (1999); Y. Daaka, L. M. Luttrell, R. J. Lefkowitz, Nature 390, 88-91 (1997)]. Not only these questions lie in the heart of hormone actions and receptor signaling but also dissecting mechanisms underlying these questions could offer therapeutic routes for refractory diseases, such as kidney injury (KI) or X-linked nephrogenic diabetes insipidus (NDI). Here, we identified that Gs-biased signaling, but not Gi activation downstream of EP4, showed beneficial effects for both KI and NDI treatments. Notably, by solving Cryo-electron microscope (cryo-EM) structures of EP3-Gi, EP4-Gs, and EP4-Gi in complex with endogenous prostaglandin E2 (PGE2)or two synthetic agonists and comparing with PGE2-EP2-Gs structures, we found that unique primary sequences of prostaglandin E2 receptor (EP) receptors and distinct conformational states of the EP4 ligand pocket govern the Gs/Gi transducer coupling selectivity through different structural propagation paths, especially via TM6 and TM7, to generate selective cytoplasmic structural features. In particular, the orientation of the PGE2 ω-chain and two distinct pockets encompassing agonist L902688 of EP4 were differentiated by their Gs/Gi coupling ability. Further, we identified common and distinct features of cytoplasmic side of EP receptors for Gs/Gi coupling and provide a structural basis for selective and biased agonist design of EP4 with therapeutic potential.

Ganoderma lucidum polysaccharide peptides GL-PPSQ2 alleviate intestinal ischemia-reperfusion injury via inhibiting cytotoxic neutrophil extracellular traps.

Ganoderma lucidum polysaccharides peptides (GLPP) are the main effective ingredients from G. lucidum (Leyss. ex Fr.) Karst with anti-inflammatory, antioxidant, and immunoregulatory activities. We extracted and characterized a novel GLPP, named GL-PPSQ2, which were found to have 18 amino acids and 48 proteins, connected by O-glycosidic bonds. The monosaccharide composition of GL-PPSQ2 was determined to be composed of fucose, mannose, galactose and glucose with a molar ratio of 1:1.45:2.37:16.46. By using asymmetric field-flow separation technique, GL-PPSQ2 were found to have a highly branched structure. Moreover, in an intestinal ischemia-reperfusion (I/R) mouse model, GL-PPSQ2 significantly increased the survival rate and alleviated intestinal mucosal hemorrhage, pulmonary permeability, and pulmonary edema. Meanwhile, GL-PPSQ2 significantly promoted intestinal tight junction, decreased inflammation, oxidative stress and cellular apoptosis in the ileum and lung. Analysis with Gene Expression Omnibus series indicates that neutrophil extracellular trap (NET) formation plays an important role in intestinal I/R injury. GL-PPSQ2 remarkedly inhibited NETs-related protein myeloperoxidase (MPO) and citrulline-Histone H3 (citH3) expression. GL-PPSQ2 could alleviate intestinal I/R and its induced lung injury via inhibiting oxidative stress, inflammation, cellular apoptosis, and cytotoxic NETs formation. This study proves that GL-PPSQ2 is a novel drug candidate for preventing and treating intestinal I/R injury.

[Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease].

The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP3R3) in renal cyst development in autosomal dominant polycystic kidney disease (ADPKD). 2-aminoethoxy-diphenyl borate (2-APB) and shRNA were used to suppress the expression of IP3R3. The effect of IP3R3 on cyst growth was investigated in Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney specific Pkd1 knockout (PKD) mouse model. The underlying mechanism of IP3R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP3R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP3R3 by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model. Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP3R3, which was accompanied by a subcellular redistribution process in which IP3R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP3R3 further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle. These results suggest that the expression and subcellular distribution of IP3R3 are involved in promoting renal cyst development, which implies IP3R3 as a potential therapeutic target of ADPKD.

Activation of NRF2 Signaling Pathway Delays the Progression of Hyperuricemic Nephropathy by Reducing Oxidative Stress.

Hyperuricemia (HUA)-induced oxidative stress is a crucial contributor to hyperuricemic nephropathy (HN), but the molecular mechanisms underlying the disturbed redox homeostasis in kidneys remain elusive. Using RNA sequencing, together with biochemical analyses, we found that nuclear factor erythroid 2-related factor 2 (NRF2) expression and nuclear localization levels were increased in early HN progression and then gradually declined below the baseline level. We identified the impaired activity of the NRF2-activated antioxidant pathway as a driver of oxidative damage in HN progression. Through nrf2 deletion, we further confirmed aggravated kidney damage in nrf2 knockout HN mice compared with HN mice. In contrast, the pharmacological agonist of NRF2 improved kidney function and alleviated renal fibrosis in mice. Mechanistically, the activation of NRF2 signaling reduced oxidative stress by restoring mitochondrial homeostasis and reducing NADPH oxidase 4 (NOX4) expression in vivo or in vitro. Moreover, the activation of NRF2 promoted the expression levels of heme oxygenase 1 (HO-1) and quinone oxidoreductase 1 (NQO1) and enhanced the antioxidant capacity of cells. Furthermore, the activation of NRF2 ameliorated renal fibrosis in HN mice through the downregulation of the transforming growth factor-beta 1 (TGF-ß1) signaling pathway and ultimately delayed the progression of HN. Collectively, these results suggested NRF2 as a key regulator in improving mitochondrial homeostasis and fibrosis in renal tubular cells by reducing oxidative stress, upregulating the antioxidant signaling pathway, and downregulating the TGF-ß1 signaling pathway. The activation of NRF2 represents a promising strategy to restore redox homeostasis and combat HN.

Ganoderma lucidum polysaccharides ameliorates D-galactose-induced aging salivary secretion disorders by upregulating the rhythm and aquaporins.

Longer-term deterioration in saliva secretion has been observed to occur in response to aging. The functional deterioration of the salivary gland damages swallowing and chewing abilities and consequently reduces life quality of the elderly. There are, however, only a few proven effective treatments for aging salivary secretion disorders. Ganoderma lucidum polysaccharide (GLP) has been applied to treat various diseases because of its safety, efficacy, and low cost. We investigated the protective effect of GLP on the submandibular gland (SMG) during aging. D-galactose (D-gal) was used to treat the aging mice, and the body weight, water consumption, saliva secretion, and flow rate were measured after 6 weeks of modeling. Micromorphological changes of the SMG were assessed by hematoxylin-eosin staining and transmission electron microscopy. RT-qPCR and Western blot were used to detect the expression of apoptotic proteins and inflammatory cytokines. Aquaporins (AQPs) and rhythmic protein expression were analyzed by immunohistochemistry and immunofluorescence. The results showed that GLP effectively promoted the expression of AQP5, AQP4, and AQP1, inhibited the release of TNF-α, IL-6, and Bax, and reduced inflammation and apoptosis. Further experiments showed that GLP promoted the up-regulation of core clock genes and proteins and restored the co-localized expression of CLOCK and AQP5 that were weakened during aging, helping to attenuate aging-induced weight loss, decreased salivation, and structural and functional damage. The findings of this work contribute to understanding the nature of age-related modifications in SMG by identifying changes in AQP5 expression and regulatory mechanisms linked to SMG dysfunction during aging. GLP is a potential drug for maintaining healthy salivary gland (SG) status and preventing SG deficiency in the elderly.

Urea Transporter Inhibitor 25a Reduces Ascites in Cirrhotic Rats.

Ascites is a typical symptom of liver cirrhosis that is caused by a variety of liver diseases. Ascites severely affects the life quality of patients and needs long-term treatment. 25a is a specific urea transporter inhibitor with a diuretic effect that does not disturb the electrolyte balance. In this study, we aimed to determine the therapeutic effect of 25a on ascites with a dimethylnitrosamine (DMN)-induced cirrhotic rat model. It was found that 100 mg/kg of 25a significantly increased the daily urine output by 60% to 97% and reduced the daily abdominal circumference change by 220% to 260% in cirrhotic rats with a water intake limitation. The 25a treatment kept the serum electrolyte levels within normal ranges in cirrhotic rats. The H&E and Masson staining of liver tissue showed that 25a did not change the cirrhotic degree. A serum biochemical examination showed that 25a did not improve the liver function in cirrhotic rats. A Western blot analysis showed that 25a did not change the expression of fibrosis-related marker protein α-SMA, but significantly decreased the expressions of type I collagen in the liver of cirrhotic rats, indicating that 25a did not reverse cirrhosis, but could slow the cirrhotic progression. These data indicated that 25a significantly reduced ascites via diuresis without an electrolyte imbalance in cirrhotic rats. Our study provides a proof of concept that urea transporter inhibitors might be developed as novel diuretics to treat cirrhotic ascites.

Protein Structure and Modification of Aquaporins.

Aquaporins (AQPs) allow water molecules and other small, neutral solutes to quickly pass through membrane. The protein structures of AQPs solved by crystallographic methods or cryo-electron microscopy technology show that AQP monomer consists of six membrane-spanning alpha-helices that form the central water-transporting pore. AQP monomers assemble to form tetramers, forming the functional units in the membrane, to transport water or other small molecules. The biological functions of AQPs are regulated by posttranslational modifications, e.g., phosphorylation, ubiquitination, glycosylation, subcellular distribution, degradation and protein interactions. Modifications of AQP combined with structural properties contribute to a better functional mechanism of AQPs. Insight into the molecular mechanisms responsible for AQP modifications as well as gating and transport properties proved to be fundamental to the development of new therapeutic targets or reliable diagnostic and prognostic biomarkers.

Transport Characteristics of Aquaporins.

Aquaporins (AQP) are a class of the integral membrane proteins. The main physiological function of AQPs is to facilitate the water transport across plasma membrane of cells. However, the transport of various kinds of small molecules by AQPs is an interesting topic. Studies using in vitro cell models have found that AQPs mediated transport of small molecules, including glycerol, urea, carbamides, polyols, purines, pyrimidines and monocarboxylates, and gases such as CO2, NO, NH3, H2O2 and O2, although the high intrinsic membrane permeabilities for these gases make aquaporin-facilitated transport not dominant in physiological mechanism. AQPs are also considered to transport silicon, antimonite, arsenite and some ions; however, most data about transport characteristics of AQPs are derived from in vitro experiments. The physiological significance of AQPs that are permeable to various small molecules is necessary to be determined by in vivo experiments. This chapter will provide information about the transport characteristics of AQPs.

Non-Transport Functions of Aquaporins.

Although it has been more than 20 years since the first aquaporin was discovered, the specific functions of many aquaporins are still under investigation, because various mice lacking aquaporins have no significant phenotypes. And in many studies, the function of aquaporin is not directly related to its transport function. Therefore, this chapter will focus on some unexpected functions of aquaporins, such the decreased tumor angiogenesis in AQP1 knockout mice, and AQP1 promotes cell migration, possibly by accelerating the water transport in lamellipodia of migrating cells. AQP transports glycerol, and water regulates glycerol content in epidermis and fat, thereby regulating skin hydration/biosynthesis and fat metabolism. AQPs may also be involved in neural signal transduction, cell volume regulation, and organelle physiology. AQP1, AQP3, and AQP5 are also involved in cell proliferation. In addition, AQPs have also been reported to play roles in inflammation in various tissues and organs. The functions of these AQPs may not depend on the permeability of small molecules such as water and glycerol, suggesting AQPs may play more roles in different biological processes in the body.

Aquaporins in Digestive System.

In this chapter, we mainly discuss the expression and function of aquaporins (AQPs) expressed in digestive system. AQPs are highly conserved transmembrane protein responsible for water transport across cell membranes. AQPs in gastrointestinal tract include four members of aquaporin subfamily: AQP1, AQP4, AQP5, and AQP8, and three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP10. In the digestive glands, especially the liver, we discuss four members of aquaporin subfamily: AQP1, AQP4, AQP5, and AQP8, three members of aquaglyceroporin subfamily: AQP7, AQP9, and AQP12. In digestive system, the abnormal expression of AQPs is closely related to the occurrence and development of a variety of diseases. AQP1 is involved in saliva secretion and fat digestion and is closely related to gastric cancer and chronic liver disease; AQP3 is involved in the diarrhea and inflammatory bowel disease; AQP4 regulates gastric acid secretion and is associated with the development of gastric cancer; AQP5 is relevant to gastric carcinoma cell proliferation and migration; AQP7 is the major aquaglyceroporin in pancreatic ß cells; AQP8 plays a role in pancreatic juice secretion and may be a potential target for the treatment of diarrhea; AQP9 plays considerable role in glycerol metabolism and hepatocellular carcinoma; Studies on the function of AQP10 and AQP12 are still limited. Further studies are necessary for specific locations and functions of AQPs in digestive system.

Aquaporins in Nervous System.

Aquaporins (AQPs) mediate water flux between the four distinct water compartments in the central nervous system (CNS). In the present chapter, we mainly focus on the expression and function of the nine AQPs expressed in the CNS, which include five members of aquaporin subfamily: AQP1, AQP4, AQP5, AQP6, and AQP8; three members of aquaglyceroporin subfamily: AQP3, AQP7, and AQP9; and one member of superaquaporin subfamily: AQP11. In addition, AQP1, AQP2, and AQP4 expressed in the peripheral nervous system are also reviewed. AQP4, the predominant water channel in the CNS, is involved both in the astrocyte swelling of cytotoxic edema and the resolution of vasogenic edema and is of pivotal importance in the pathology of brain disorders such as neuromyelitis optica, brain tumors, and neurodegenerative disorders. Moreover, AQP4 has been demonstrated as a functional regulator of recently discovered glymphatic system that is a main contributor to clearance of toxic macromolecule from the brain. Other AQPs are also involved in a variety of important physiological and pathological process in the brain. It has been suggested that AQPs could represent an important target in treatment of brain disorders like cerebral edema. Future investigations are necessary to elucidate the pathological significance of AQPs in the CNS.

Aquaporins in Urinary System.

There are at least eight aquaporins (AQPs) expressed in the kidney. Including AQP1 expressed in proximal tubules, thin descending limb of Henle and vasa recta; AQP2, AQP3, AQP4, AQP5, and AQP6 expressed in collecting ducts; AQP7 expressed in proximal tubules; AQP8 expressed in proximal tubules and collecting ducts; and AQP11 expressed in the endoplasmic reticulum of proximal tubular epithelial cells. Over years, researchers have constructed different AQP knockout mice and explored the effect of AQP knockout on kidney function. Thus, the roles of AQPs in renal physiology are revealed, providing very useful information for addressing fundamental questions about transepithelial water transport and the mechanism of near isoosmolar fluid reabsorption. This chapter introduces the localization and function of AQPs in the kidney and their roles in different kidney diseases to reveal the prospects of AQPs in further basic and clinical studies.

Aquaporins in Reproductive System.

AQP0-12, a total of 13 aquaporins are expressed in the mammalian reproductive system. These aquaporins mediate the transport of water and small solutes across biofilms for maintaining reproductive tract water balance and germ cell water homeostasis. These aquaporins play important roles in the regulation of sperm and egg cell production, maturation, and fertilization processes. Impaired AQP function may lead to diminished male and female fertility. This review focuses on the distribution, function, and regulation of AQPs throughout the male and female reproductive organs and tracts. Their correlation with reproductive success, revealing recent advances in the physiological and pathophysiological roles of aquaporins in the reproductive system.

Aquaporins in Immune System.

Recent studies have shown that at least six aquaporins (AQPs), including AQP1, AQP3, AQP4, AQP5, AQP7, and AQP9, are expressed in immune system. These AQPs distribute in lymphocytes, macrophages, dendritic cells, and neutrophils, and mediate water and glycerol transportation in these cells, which play important roles in innate and adaptive immune functions. Immune system plays important roles in body physiological functions and health. Therefore, understanding the association between AQPs and immune system may provide approaches to prevent and treat related diseases. Here we will discuss the expression and physiological functions of AQPs in immune system and summarize recent researches on AQPs in immune diseases.

Aquaporins in Edema.

One of the most prevalent indications of water-electrolyte imbalance is edema. Aquaporins (AQPs) are a protein family that can function as water channels. Osmoregulation and body water homeostasis are dependent on the regulation of AQPs. Human kidneys contain nine AQPs, five of which have been demonstrated to have a role in body water balance: AQP1, AQP2, AQP3, AQP4, and AQP7. Water imbalance is connected with AQP dysfunction. Hyponatremia with elevated AQP levels can accompany edema, which can be caused by disorders with low effective circulating blood volume and systemic vasodilation, such as congestive heart failure (CHF), hepatic cirrhosis, or the syndrome of incorrect antidiuretic hormone secretion (SIADH). In CHF, upregulation of AQP2 expression and targeting is critical for water retention. AQP2 is also involved in aberrant water retention and the formation of ascites in cirrhosis of the liver. Furthermore, water retention and hyponatremia in SIADH are caused by increased expression of AQP2 in the collecting duct. Fluid restriction, demeclocycline, and vasopressin type-2 receptor antagonists are widely utilized to treat edema. The relationship between AQPs and edema is discussed in this chapter.