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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 C. Corless, Robert C. Speth and Susan P. Bagby^*

Departments of *Medicine and Pathology, Oregon Health & Science University and Portland VA Medical Center, Portland, Oregon, and Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington.

Correspondence to: Dr. Susan P. Bagby, Division of Nephrology & Hypertension, Oregon Health and Science University, 3314 SW US Veterans Hospital Rd., Suite 262, Portland, OR 97239-2940. Phone: 503-494-8490; Fax: 503-494-5330; E-mail: bagbys{at}ohsu.edu

ABSTRACT. Autosomal dominant polycystic kidney disease (ADPKD) 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.

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