MECHANISMS OF CYCLOSPORINE NEPHROTOXICITY

Project: Research project

Project Details

Description

The long-term goal is to elucidate the mechanisms responsible for
functional abnormalities present in the early phase of cyclosporine-induced
nephrotoxicity (CIN). The specific aims are:

1. To determine if the renal vasoactive hormones (renin-angiotensin,
prostaglandin, and kallikrein-kinin systems) and/or the sympathetic nervous
system mediate the reduced rates of filtration (GFR) and renal blood flow
(RBF) characteristic of CIN.

2. To determine whether the glomerular capillary ultrafiltration
coefficient (Kf) is reduced in CIN.

A rat model of early CIN with both functional and histomorphologic
characteristics similar to those in humans will be used. Measurements will
be made in awake, chronically cyclosporine treated animals of daily GRF by
inulin clearance and renovasoactive hormone activities in blood and urine.
Also, measurements of GFR by clearance and RBF by electromagnetic flow
probe will be made in anesthetized control and acutely cyclosporine-treated
rats, both before and after acute pharmacologic blockade of angiotensin II,
renal kinins, and renal prostaglandins by infusions of saralasin,
indomethacin or aprotinin. The contribution of the sympathetic nervous
system will also be evaluated by acute renal denervation studies. GFR and
RBF will also be studied in rats simultaneously treated with cyclosporine
and a specific blocker for 7 days. The determinants of glomerular
ultrafiltration will be measured with standard micropuncture methodology in
the chronic model of CIN. Hydrostatic pressures will be measured in
proximal tubules and efferent arterioles, as well as in stop-flow
nephrons. Nephron filtration rates and protein concentrations in systemic
and efferent arteriolar plasma will be measured; arteriolar resistances and
Kf will be derived. The results of this project will elucidate the
mechanisms responsible for the functional abnormalities in early CIN. This
information may provide a scientific basis for the design of effective
therapeutic interventions to treat and prevent the adverse effects of this
increasingly utilized immunosuppressant.
StatusFinished
Effective start/end date1/1/906/30/90

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Nephrology
  • Physiology (medical)
  • Physiology
  • Toxicology
  • Pharmacology

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