Kenneth D. Mitchell, Ph.D.

Research activities are oriented towards evaluating the role of angiotensin II (ANG II) in the regulation of renal hemodynamics and tubular reabsorption rate. Emphasis is focused on determining the contribution of ANG II-dependent alterations in renal hemodynamics and tubular reabsorptive function to the development and maintenance of various forms of hypertension. Current studies primarily utilize Cyp1a1-Ren2 transgenic rats [TGR(Cyp1a1Ren2)] with inducible expression of the mouse Ren2 renin gene. A variety of in vivo renal clearance and micropuncture procedures are employed to evaluate whole kidney and single nephron hemodynamics and tubular reabsorptive function in anesthetized normotensive and hypertensive rats.

Whole kidney clearance procedures used include inulin and para-aminohippurate clearances for the determination of glomerular filtration rate and renal plasma flow, respectively. In addition, measurements of the renal blood flow responses (using transit time flow probes) to both intravenous and selective intrarenal arterial administration of various vasoactive agents are used to assess renal vascular responsiveness in normotensive and hypertensive rats. Specific micropuncture procedures that are routinely used in the laboratory include: 1) collection of tubular fluid samples from superficial nephrons for determination of single nephron glomerular filtration rate and tubular reabsorptive function, 2) collection of blood samples from surface peritubular capillaries for determination of postglomerular plasma protein concentration and single nephron plasma flow, 3) measurement of hydrostatic pressures in superficial tubules and peritubular capillaries, 4) microperfusion of superficial tubules and peritubular capillaries, and 5) measurement of tubuloglomerular feedback mediated changes in both single nephron glomerular filtration rate and proximal tubule stop flow pressure. In addition, procedures for the macro- and microanalysis of plasma, urine, and tubular fluid samples collected from the clearance and micropuncture experiments are routinely employed. Furthermore, radioimmunoassay procedures are also used to determine the levels of angiotensin peptides in plasma, kidney tissue, and tubular fluid samples collected from normotensive and hypertensive rats.

Research efforts in my laboratory are currently oriented towards 1) evaluation of the role of platelet-derived growth factor (PDGF) in mediating the renal hemodynamic and morphological derangements that occur in slowly progressive ANG II-dependent hypertension and in ANG II-dependent malignant hypertension, 2) determination of the effects of chronic and acute direct renin inhibition on the renal hemodynamic and morphological derangements in slowly progressive ANG II-dependent hypertension and in ANG II-dependent malignant hypertension, 3) assessment of the effects of alterations in dietary salt intake on the pathogenesis of slowly progressive ANG II-dependent hypertension and ANG II-dependent malignant hypertension, and 4) determination of the ANG II-independent renal hemodynamics and morphological changes in ANG II-dependent hypertension. Collectively, the research performed in my laboratory is designed to provide new information regarding the mechanisms responsible for mediating the renal functional and morphological derangements in ANG II-dependent hypertension.