title: DL-propargylglycine reduces blood pressure and renal injury but increases kidney weight in angiotensin-II infused rats.
abstract: Hydrogen sulfide (H2S), carbon monoxide (CO) and nitric oxide (NO) share signaling and vasorelaxant properties and are involved in proliferation and apoptosis. Inhibiting NO production or availability induces hypertension and proteinuria, which is prevented by concomitant blockade of the H2S producing enzyme cystathionine γ-lyase (CSE) by d,l-propargylglycine (PAG). We hypothesized that blocking H2S production ameliorates Angiotensin II (AngII)-induced hypertension and renal injury in a rodent model. Effects of concomitant administration of PAG or saline were therefore studied in healthy (CON) and AngII hypertensive rats. In CON rats, PAG did not affect systolic blood pressure (SBP), but slightly increased proteinuria. In AngII rats PAG reduced SBP, proteinuria and plasma creatinine (180 ± 12 vs. 211 ± 19 mmHg; 66 ± 35 vs. 346 ± 92 mg/24 h; 24 ± 6 vs. 47 ± 15 μmol/L, respectively; p < 0.01). Unexpectedly, kidney to body weight ratio was increased in all groups by PAG (p < 0.05). Renal injury induced by AngII was reduced by PAG (p < 0.001). HO-1 gene expression was increased by PAG alone (p < 0.05). PAG increased inner cortical tubular cell proliferation after 1 week and decreased outer cortical tubular nucleus number/field after 4 weeks. In vitro proximal tubular cell size increased after exposure to PAG. In summary, blocking H2S production with PAG reduced SBP and renal injury in AngII infused rats. Independent of the cardiovascular and renal effects, PAG increased HO-1 gene expression and kidney weight. PAG alone increased tubular cell size and proliferation in-vivo and in-vitro. Our results are indicative of a complex interplay of gasotransmitter signaling/action of mutually compensatory nature in the kidney.
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
authors.forename: Nynke R
authors.initials: NR
authors.lastname: Oosterhuis
authors.affiliation: UMC Groningen, Pathology and Biomedical Biology, Hanzeplein 1, 9700 RB Groningen, Netherlands.
authors.forename: Anne-Roos S
authors.initials: AR
authors.lastname: Frenay
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands; Wageningen University, Division of Toxicology, Droevendaalsesteeg 4, 6708 PB Wageningen, Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Wesseling
authors.affiliation: UMC Groningen, Pathology and Biomedical Biology, Hanzeplein 1, 9700 RB Groningen, Netherlands; UMC Groningen, Surgery, Hanzeplein 1, 9700 RB Groningen, Netherlands.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Snijder
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
authors.forename: Gisela G
authors.initials: GG
authors.lastname: Slaats
authors.affiliation: UMC Groningen, Nephrology, Hanzeplein 1, 9700 RB Groningen, Netherlands.
authors.forename: Saleh
authors.initials: S
authors.lastname: Yazdani
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
authors.affiliation: UMC Utrecht, Nephrology and Hypertension, Heidelberglaan 100, 3584 CX Utrecht, Netherlands. Electronic address: j.a.joles@umcutrecht.nl.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.affiliation: UMC Groningen, Pathology and Biomedical Biology, Hanzeplein 1, 9700 RB Groningen, Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: van Goor
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism*; D000480:Alkynes / Q000008:administration & dosage / Q000494:pharmacology*; D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D049109:Cell Proliferation; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D009569:Nitric Oxide; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000480:Alkynes; D000804:Angiotensin II; D009569:Nitric Oxide; C009055:propargylglycine; D051547:Heme Oxygenase-1; D005998:Glycine; D006862:Hydrogen Sulfide
keywords: Angiotensin-II; Hydrogen sulfide; Hypertension; Kidney weight; Proteinuria; dl-Propargylglycine