Chymase-like Angiotensin II-Generating Activity in End-Stage Human Autosomal Dominant Polycystic Kidney Disease

Elizabeth A. Mcpherson, Zaiming Luo, Rachel A. Brown, Linda S. Lebard, Christopher Corless, Robert C. Speth, Susan Bagby

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease (AD-PKD) is characterized by exuberant inflammation and fibrosis, a process believed to contribute to progressive loss of normal renal function. Despite early-onset hypertension and intrarenal renin/angiotensin II (AngII) activation, angiotensin-converting enzyme (ACE) inhibition does not consistently confer renal protection in ADPKD. The hypothesis was that mast cells within the inflammatory interstitium release chymase, an enzyme capable of efficient conversion of AngI to AngII, providing an ACE-independent route of AngII generation. End-stage ADPKD renal tissue extracts and cyst fluids were assayed for time-dependent, chymostatin-inhibitable conversion of 125I-AngI to 125I-AngII under conditions of ACE and aminopeptidase inhibition by means of HPLC. Thirteen of 14 ADPKD kidney extracts exhibited chymase-like AngII-generating capacity; calculated initial reaction rates averaged 3.9 ± 2.9 fmol AngII/min/μg protein with a mean maximal conversion of 55% ± 30% of added substrate. AngII-generating activity was both protein and substrate dependent. All five cyst fluid samples were negative. Chymase-like activity was detectable in only three of six non-ADPKD kidney extracts. Immunoreactive chymase protein was present in/around mast cells within the fibrotic renal interstitium in all samples. Findings demonstrate for the first time the presence of mast cells, mast cell-associated immunoreactive chymase protein, and chymase-like AngII generating capacity in ADPKD cystic kidneys. Results support the potential for ACE-independent AngII generation and for mast cell-initiated inflammatory processes in ADPKD, each with therapeutic implications for ADPKD renal progression.

Original languageEnglish (US)
Pages (from-to)493-500
Number of pages8
JournalJournal of the American Society of Nephrology
Volume15
Issue number2
DOIs
StatePublished - Feb 2004

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Chymases
Autosomal Dominant Polycystic Kidney
Angiotensin II
Mast Cells
Kidney
Peptidyl-Dipeptidase A
Cyst Fluid
Proteins
Cystic Kidney Diseases
Aminopeptidases
Tissue Extracts
Renin
Fibrosis
High Pressure Liquid Chromatography
Hypertension
Inflammation

ASJC Scopus subject areas

  • Nephrology

Cite this

Chymase-like Angiotensin II-Generating Activity in End-Stage Human Autosomal Dominant Polycystic Kidney Disease. / Mcpherson, Elizabeth A.; Luo, Zaiming; Brown, Rachel A.; Lebard, Linda S.; Corless, Christopher; Speth, Robert C.; Bagby, Susan.

In: Journal of the American Society of Nephrology, Vol. 15, No. 2, 02.2004, p. 493-500.

Research output: Contribution to journalArticle

Mcpherson, Elizabeth A. ; Luo, Zaiming ; Brown, Rachel A. ; Lebard, Linda S. ; Corless, Christopher ; Speth, Robert C. ; Bagby, Susan. / Chymase-like Angiotensin II-Generating Activity in End-Stage Human Autosomal Dominant Polycystic Kidney Disease. In: Journal of the American Society of Nephrology. 2004 ; Vol. 15, No. 2. pp. 493-500.
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