Loss of Prolyl Carboxypeptidase in Two-Kidney, One-Clip Goldblatt Hypertensive Mice

Abstract

It is well documented that angiotensin (Ang) II contributes to kidney disease progression. The protease prolyl carboxypeptidase (PRCP) is highly expressed in the kidney and may be renoprotective by degrading Ang II to Ang-(1-7). The aim of the study was to investigate whether renal PRCP protein expression and activity are altered in two-kidney, one-clip (2K1C) Goldblatt hypertensive mice. Left renal artery was constricted by using 0.12 mm silver clips. Blood pressure was measured using telemetry over the eleven weeks of study period and revealed an immediate increase in 2K1C animals during the first week of clip placement which was followed by a gradual decrease to baseline blood pressure. Similarly, urinary albumin excretion was significantly increased one week after 2K1C and returned to baseline levels during the following weeks. At 2 weeks and at the end of the study, renal pathologies were exacerbated in the 2K1C model as revealed by a significant increase in mesangial expansion and renal fibrosis. Renal PRCP expression and activity were significantly reduced in clipped kidneys. Immunofluorescence revealed the loss of renal tubular PRCP but not glomerular PRCP. In contrast, expression of prolyl endopeptidase, another enzyme capable of converting Ang II into Ang-(1-7), was not affected, while angiotensin converting enzyme was elevated in unclipped kidneys and renin was increased in clipped kidneys. Results suggest that PRCP is suppressed in 2K1C and that this downregulation may attenuate renoprotective effects via impaired Ang II degradation by PRCP.

Identification of novel molecular signatures of IgA nephropathy through an integrative -omics analysis

“…The selected validation candidate - prolylcarboxypeptidase (PRCP), regulates blood pressure and electrolyte balance, cleaving Ang II or Ang III 75 . Along these lines, PRCP deficiency was reported to impair Ang II degradation and thus, its increase may be associated with hypertension and glomerular lesions 76 , 77 . PRCP has also been shown to be an activator of the cell matrix-associated pre-kallikrein and molecular events upstream of the fibrinolytic system 78 .…”

Effects of Angiotensin II Type 1A Receptor on ACE2, Neprilysin and KIM-1 in Two Kidney One Clip (2K1C) Model of Renovascular Hypertension

“…Radio-telemetry probes were used to measure blood pressure in freely moving mice as described before ( Grobe et al, 2015 ). Briefly, under isoflurane anesthesia, an incision was made on the neck and a sterile catheter of the telemetry transducer/transmitter (model TA11PA-C10, Data Sciences International, St Paul, MN, United States) was inserted into the carotid artery and secured with 5.0-gauge silk suture (Arosurgical, Newport Beach, CA, United States).…”

“…The two-kidney, one-clip (2K1C) Goldblatt hypertensive mouse model involves the constriction of renal arteries which leads to increased systolic blood pressure and development of renovascular hypertension ( Goldblatt et al, 1934 ). The stenosis of the renal artery activates the renin angiotensin system (RAS) and is responsible for the upregulation of renin during the first few weeks ( Prieto-Carrasquero et al, 2008 ; Grobe et al, 2015 ; Kim et al, 2016 ) which contributes to the upregulation of angiotensin II (Ang II) ( Prieto et al, 2011 ). The Ang II-mediated hypertension through the AT1 receptor occurs during the entire period of renal artery stenosis regardless of the plasma renin activity ( Wilcox et al, 1996 ).…”

“…The 2K1C Goldblatt model is a useful tool to determine factors that might play a role in the development of cardiovascular and renal diseases in the absence of hyperglycemia and insulin resistance. Our previous study in the 2K1C Goldblatt hypertensive mice showed loss of the Ang-(1–7) forming enzyme prolyl carboxypeptidase which could impair the degradation of renal Ang II and contribute to kidney injury ( Grobe et al, 2015 ). Recently, two other Ang-(1–7) forming enzymes, angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP), have gained recognition as important regulators of cardiovascular and renal function.…”

Successful long-term effects of direct renin inhibitor aliskiren in a patient with atherosclerotic renovascular hypertension

“…Unilateral renal artery stenosis in humans is compatible with the experimental animal model of "Two-kidney one-clip (2K1C) hypertension". In the 2K1C model, PRA is secreted from the clipped ischemic kidney while the unclipped kidney stays hyperfiltrable [12]. Using ACE-Is or ARBs for this type could result in a rapid decrease in RAAS activity, promoting natriuresis, decreasing glomerular filtration rate, and secondarily, stimulating PRA.…”