NYMC Student Theses and Dissertations

Date of Award

8-2024

Document Type

Master's Thesis - Restricted (NYMC/Touro only) Access

Degree Name

Master of Science

Department

Basic Medical Sciences

First Advisor

Nicholas Ferreri Ph.D

Second Advisor

Shoujin Hao Ph.D

Third Advisor

Victor Garcia Ph.D

Abstract

To determine the effects that renal derived local TNF-a production may have in a state of chronic inflammation associated with an increase in blood pressure, TNF-a was selectively silenced in the kidney by intrarenal administration of lentivirus (U6-TNF-ex4) 3 days before administration of Angiotensin II. Challenge with Ang II infused over 14 days by osmotic minipump increased MAP, the renal production of TNF-a, and TNFR2 expression in renal cortex outer medulla. These changes were associated with a concomitant decrease in NKCC2A mRNA accumulation while NKCC2B mRNA levels remained unchanged. MAP was elevated significantly in mice treated with Ang II + U6-TNF-ex4 versus mice treated with Ang II alone. Remarkably, lentivirus silencing of TNF, which specifically inhibits resident cells of the kidney, before the administration of Ang II was sufficient to effectively abolish TNF mRNA levels in the kidney. The expression of NKCC2A was increased significantly in the cortex of the Ang II + U6-TNF-ex4 group compared with the control group (Ang II alone) while NKCC2B expression was decreased in the cortex of the U6- TNF-ex4 group. Expression for both TNF receptors was determined by qRT-PCR; levels of TNFR1 mRNA were unchanged in the U6-TNF-ex4 group while levels for TNFR2 mRNA were reduced compared with the control group. These preliminary findings suggest that local TNF- a produced in the kidney prior to a hypertensive challenge with Ang II plays a protective role against further increases in blood pressure. The concomitant changes in NKCC2 isoform and TNFR2 expression may be part of the mechanism by which TNF plays a role in blood pressure and renal function in response to ANG II.

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