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Decreased O2 consumption by PMNL from humans and rats with CRF: role of secondary hyperparathyroidism
M Kiersztejn1, M Smogorzewski, P Thanakitcharu
1Department of Medicine, University of Southern California School of Medicine, Los Angeles.
Abstract:
Bactericidal ability of polymorphonuclear leukocytes (PMNL) is impaired in chronic renal failure (CRF). This function of PMNL is mediated by the generation of oxidizing radicals and the latter event requires O2 consumption by these cells. The present study examined both basal and FMLP-stimulated rise in cytosolic calcium ([Ca2+]i) and O2 consumption of PMNL from normal subjects and hemodialysis patients and from CRF rats, and evaluated the potential role of secondary hyperparathyroidism of CRF on these properties of PMNL. Basal levels of [Ca2+]i were significantly higher, and FMLP-induced increments in [Ca2+]i were significantly lower in PMNL of both humans and rats with CRF than in normals. Basal and FMLP-stimulated O2 consumption were significantly lower in CRF subjects and rats than in normals. These derangements were prevented by prior parathyroidectomy of CRF rats or by their treatment with verapamil from day one of CRF. Also, therapy of rats with pre-existing CRF with this drug reversed the abnormalities in [Ca2+]i and in O2 consumption of PMNL. The data indicate that: (1) CRF is associated with derangements in the homeostasis of [Ca2+]i of PMNL and their oxygen consumption, (2) these abnormalities are, most likely, mediated by the state of secondary hyperparathyroidism of CRF, and (3) verapamil, which blocks the PTH-induced entry of calcium into cells, and prevents as well as reverses these PMNL dysfunctions. These results implicate the excess PTH of CRF in the genesis of the defective bactericidal function of PMNL, and assign a new dimension to PTH toxicity in CRF.
Insights
Chronic renal failure impairs polymorphonuclear leukocyte (PMNL) function due to altered calcium and oxygen consumption. Secondary hyperparathyroidism is implicated, but verapamil treatment shows promise in correcting these defects.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Polymorphonuclear leukocytes (PMNL) are crucial for bacterial killing, but their function is compromised in chronic renal failure (CRF).
- This impairment is linked to reduced generation of oxidizing radicals, dependent on oxygen consumption by PMNL.
- Secondary hyperparathyroidism is a common complication of CRF.
Purpose of the Study:
- To investigate alterations in cytosolic calcium ([Ca2+]i) and oxygen consumption in PMNL from CRF patients and rats.
- To evaluate the role of secondary hyperparathyroidism in these PMNL dysfunctions.
- To assess the therapeutic potential of verapamil in correcting these CRF-associated PMNL abnormalities.
Main Methods:
- Measurement of basal and FMLP-stimulated [Ca2+]i and O2 consumption in PMNL from normal and CRF subjects/rats.
- Assessment of PMNL function following parathyroidectomy or verapamil treatment in CRF rats.
- Evaluation of verapamil's effect on established CRF-induced PMNL dysfunction.
Main Results:
- PMNL from CRF individuals exhibited higher basal [Ca2+]i and lower FMLP-stimulated [Ca2+]i compared to normals.
- Both basal and stimulated O2 consumption were significantly reduced in CRF PMNL.
- These abnormalities were prevented or reversed by parathyroidectomy or verapamil treatment.
Conclusions:
- CRF disrupts PMNL calcium homeostasis and oxygen consumption.
- Secondary hyperparathyroidism in CRF is a likely mediator of these PMNL dysfunctions.
- Verapamil effectively corrects PMNL dysfunction in CRF, suggesting a role for excess parathyroid hormone (PTH) in impaired bacterial defense.