title: Mechanisms of angiotensin II-enhanced connecting tubule glomerular feedback.
abstract: Increasing Na delivery to the connecting tubule (CNT) causes afferent arteriole (Af-Art) dilation, a process we call CNT glomerular feedback (CTGF). Angiotensin II (ANG II) in the CNT lumen enhances CTGF via PKC. We hypothesized that luminal ANG II stimulates CTGF via activation of protein kinase C (PKC), NADPH oxidase 2 (NOX2), and enhanced production of superoxide (O(2)(-)). Rabbit Af-Arts and adherent CNTs were microdissected and microperfused in vitro. Dilation of the Af-Art was induced by increasing luminal CNT NaCl from 0 to 5, 10, 30, 45, and 80 mM, and the concentration of NaCl that elicited a half-maximal response (EC(50)) was calculated. Compared with vehicle, adding ANG II (10(-9) M) to the CNT lumen reduced EC(50) from 37 ± 3 to 14 ± 1 mM (P < 0.001), indicating ANG II potentiates CTGF. In the presence of ANG II, the O(2)(-) scavenger tempol (10(-4) M) increased EC(50) from 20 ± 4 to 41 ± 3 mM (P < 0.01), the NOX inhibitor apocynin (10(-5) M) increased EC(50) from 17 ± 2 to 39 ± 4 mM (P < 0.01), and the specific NOX2 inhibitor gp91ds-tat (10(-5) M) increased EC(50) from 19 ± 2 to 34 ± 2 mM (P < 0.01). However, tempol, apocynin, and gp91ds-tat had no effect on CTGF in the absence of ANG II. Compared with vehicle, the PKC activator PMA (2 × 10(-7) M) decreased EC(50) from 35 ± 2 to 14 ± 1 (P < 0.001). In the presence of PMA, tempol increased EC(50) from 14 ± 2 to 35 ± 2 mM (P < 0.01). We conclude the PKC/NOX2/O(2)(-) pathway mediates the enhancement of CTGF by luminal ANG II but it does not participate in CTGF in the absence of ANG II.
authors.affiliation: Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202, USA.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Ren
authors.forename: Martin A
authors.initials: MA
authors.lastname: D'Ambrosio
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Edward L
authors.initials: EL
authors.lastname: Peterson
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Garvin
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D025461:Feedback, Physiological / Q000187:drug effects* / Q000502:physiology*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000502:physiology*; D007684:Kidney Tubules / Q000187:drug effects / Q000502:physiology*; D023421:Models, Animal; D019255:NADPH Oxidases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012965:Sodium Chloride / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D013481:Superoxides; D000804:Angiotensin II; D012965:Sodium Chloride; D019255:NADPH Oxidases; D011493:Protein Kinase C