Aquaporins in Renal Diseases

Abstract

Aquaporins (AQPs) are a family of highly selective transmembrane channels that mainly transport water across the cell and some facilitate low-molecular-weight solutes. Eight AQPs, including AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, and AQP11, are expressed in different segments and various cells in the kidney to maintain normal urine concentration function. AQP2 is critical in regulating urine concentrating ability. The expression and function of AQP2 are regulated by a series of transcriptional factors and post-transcriptional phosphorylation, ubiquitination, and glycosylation. Mutation or functional deficiency of AQP2 leads to severe nephrogenic diabetes insipidus. Studies with animal models show AQPs are related to acute kidney injury and various chronic kidney diseases, such as diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma. Experimental data suggest ideal prospects for AQPs as biomarkers and therapeutic targets in clinic. This review article mainly focuses on recent advances in studying AQPs in renal diseases.

Keywords: acute kidney injury; aquaporin; diabetic nephropathy; nephrogenic diabetes insipidus; polycystic kidney disease; renal cell carcinoma; vasopressin.

Figure 1

Expression localization of AQPs in kidney. AQP1 is located in proximal tubule, descending thin limbs of Henle, and vasa recta; AQP2, AQP3, AQP4, AQP5 and AQP6 are in the collecting duct; AQP7 and AQP11 are expressed in proximal tubule.

Figure 2

Schematic summary of main regulatory mechanisms of AQP2. AVP binding to V2R stimulates the activation of canonical cAMP/PKA signaling and increases the expression and phosphorylation of AQP2 at S256 and S269, leading to the apical membrane trafficking of AQP2. Activation of TGR5 increases the activation of PKA to induce the expression of AQP2. H₂S increases AQP2 expression via enhancing the activation of cAMP/PKA signaling. Besides, Wnt5a binds to Fzd receptors and increases the level of intracellular calcium, which stimulates calcineurin and increases the expression and phosphorylation of AQP2. Erlotinib promotes AQP2 expression in the apical membrane by increasing the phosphorylation of AQP2 and reducing its endocytosis and degradation. The translocation of AP-1, CREB, C/EBPβ, and NFAT into the nucleus regulates the expression of AQP2.

Figure 3

NDI caused by AQP2 mutation. (A) The immunofluorescence of AQP2 in kidneys of wild-type (left) and inducible AQP2^T126M/− mice (right). (B) Immunoblot of AQP2 from wild-type and inducible AQP2^T126M/− mice. (C) AQP2 protein immunoblot of kidney homogenates from wild-type and AQP2^T126M/− mice treated with or without Hsp90 inhibitor 17-AAG. (D) Urine osmolality in wild-type, AQP2 knockout, and inducible AQP2^T126M/− mice given free access to food and water before and after 17-AAG treatment. The block, solid ball, and triangle represent wild-type mice, AQP2^T126M/− mice, and AQP2^−/− mice, respectively (adapted from Ref [38]).

Figure 4

AQP3 deficiency aggravates IR injury. (A) Serum BUN level in wild-type and AQP3^−/− mice after reperfusion following 30 min ischemia. (B) Serum creatinine level in wild-type and AQP3^−/− mice after reperfusion following 30 min ischemia. (C) The activity of SOD in renal tissue. (D) The level of MDA in renal tissue. (E) Representative outer medullary collecting duct (OMCD) images of H&E staining of wild-type and AQP3^−/− kidneys after sham surgery or I/R. Black arrow represents dilated collecting ducts. (F) Different protein expression level of kidneys after reperfusion was detected by Western blot (adapted from Ref [56]).

Figure 5

AQP1 retards renal cyst development. (A) Representative images of MDCK and AQP1-MDCK cyst from day 4 to day 14. (B) Representative images of AQP1^+/− and AQP1^−/− embryonic kidney cyst from day 0 to day 6. (C) Representative images of wild-type, PKD, and AQP1^−/− PKD kidneys. (D) Coimmunoprecipitation with anti-AQP1 showing the protein AQP1 interaction with β-catenin, GSK3β, LRP6, and Axin1 in AQP1-MDCK cells. M and A indicate MDCK cells and AQP1-MDCK cells, respectively. (E) Schematic of AQP1 regulating β-catenin (adapted from Ref [79]).