title: Mechanisms of connecting tubule glomerular feedback enhancement by aldosterone.
abstract: Connecting tubule glomerular feedback (CTGF) is a mechanism where an increase in sodium (Na) concentration in the connecting tubule (CNT) causes the afferent arteriole (Af-Art) to dilate. We recently reported that aldosterone within the CNT lumen enhances CTGF via a nongenomic effect involving GPR30 receptors and sodium/hydrogen exchanger (NHE), but the signaling pathways of this mechanism are unknown. We hypothesize that aldosterone enhances CTGF via cAMP/protein kinase A (PKA) pathway that activates protein kinase C (PKC) and stimulates superoxide (O2-) production. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing the CNT luminal NaCl. We found that the main effect of aldosterone was to sensitize CTGF and we analyzed data by comparing NaCl concentration in the CNT perfusate needed to achieve half of the maximal response (EC50). During the control period, the NaCl concentration that elicited a half-maximal response (EC50) was 37.0 ± 2.0 mmol/l; addition of aldosterone (10-8mol/l) to the CNT lumen decreased EC50to 19.3 ± 1.3 mmol/l (P ≤ 0.001 vs. Control). The specific adenylyl cyclase inhibitor 2',3'-dideoxyadenosine (ddA; 2 × 10-4mol/l) and the PKA inhibitor H-89 dihydrochloride hydrate (H-89; 2 × 10-6mol/l) prevented the aldosterone effect. The selective PKC inhibitor GF109203X (10-8mol/l) also prevented EC50reduction caused by aldosterone. CNT intraluminal addition of O2-scavenger tempol (10-4mol/l) blocked the aldosterone effect. We conclude that aldosterone inside the CNT lumen enhances CTGF via a cAMP/PKA/PKC pathway and stimulates O2-generation and this process may contribute to renal damage by increasing glomerular capillary pressure.
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
authors.forename: YiLin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
authors.forename: Branislava
authors.initials: B
authors.lastname: Janic
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Kutskill
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.affiliation: Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and ocarret1@hfhs.org.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D025461:Feedback, Physiological / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011493:Protein Kinase C / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D012965:Sodium Chloride / Q000378:metabolism*; D013113:Spin Labels; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D003497:Cyclic N-Oxides; D007546:Isoquinolines; D013113:Spin Labels; D013449:Sulfonamides; D012965:Sodium Chloride; D000450:Aldosterone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C001803:tempol
keywords: PKA inhibitor; arterioles; distal kidney tubules; superoxide