Graduation Year

2019

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Medical Sciences

Major Professor

Ruisheng Liu, M.D., Ph.D.

Committee Member

Jerome Breslin, Ph.D.

Committee Member

Javier Cuevas, Ph.D.

Committee Member

Alfredo M. Peguero-Rivera, M.D.

Committee Member

Timo Rieg, M.D., Ph.D.

Committee Member

Kay-Pong D. Yip, Ph.D.

Keywords

Diabetes,, Hyperfiltration, Hypertension, Renal Hemodynamics

Abstract

In the present study, we investigated the pathophysiological mechanisms of the hemodynamic alteration in diabetes. Glomerular hyperfiltration occurs in the early stage of diabetes mellitus and has been recognized to promote the pathogenesis of diabetic nephropathy. We determine the role of TGF response and the vascular tone of Af-Art in diabetic hyperfiltration and we found that 1) tubular high glucose directly activates NOS1 and increases NO generation in the macula densa, which inhibits TGF response and increases GFR; 2) high glucose dilates renal Af-Art through GLUT1 and mediated by NOS3-derived NO generation; 3) in diabetes, blunted TGF mediated by NOS1 in the macula densa promotes glomerular hyperfiltration. The prevalence of hypertension is much higher in diabetic subjects than non-diabetic population. We studied the potential mechanisms of blood pressure regulation in diabetes, including TGF response and renal afferent arteriolar response to vasoconstrictors, and we found that 1) inadequate NOS1 in the macula densa enhances TGF, which restricts glomerular hyperfiltration and induces hypertension in diabetes; 2) hemodynamic responses to ANG II is increased in diabetes, which is associated with increased expression and activity of AT1 receptors in the Af-Art; 3) Ang II upregulates the expression and activity of Nox2 and Nox4 in the macula densa, which enhances TGF response.

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