ORCID ID

0009-0003-7603-053X

Pharmacodynamic Effects of ZSJ-0228 on Complement Protein Deposition In The Kidneys of Focal Segmental Glomerulosclerosis-Afflicted Mice.

Graduation Date

Spring 5-4-2024

Document Type

Thesis

Degree Name

Master of Science (MS)

Programs

Pharmaceutical Sciences

First Advisor

Dong Wang, PhD

Second Advisor

Geoffrey Thiele, PhD

Third Advisor

Joseph Vetro, PhD

MeSH Headings

Nephrology, Rheumatology, Internal Medicine

Abstract

Chronic inflammation, when left untreated, may result in significant morbidity and in severe cases, mortality. While glucocorticoids (GCs) are still being extensively used clinically as a class of very potent anti-inflammatory agents, they are also notorious for diverse adverse side effects. To mitigate these side effects, we have developed a polyethylene glycol (PEG)-based prodrug (ZSJ-0228) of dexamethasone (Dex). When tested on rodent models of Lupus Nephritis and Focal Segmental Glomerulosclerosis (FSGS), ZSJ-0228 was found to provide potent and sustained therapeutic efficacy without any detectable typical GC-associated side effects. Given ZSJ-0228’s transient renal exposure after systemic administration, it is yet to be revealed how such unique pharmacokinetic behavior would produce sustained resolution of nephritis. Therefore, the focus of this thesis is to understand if the nephrotropic ZSJ-0228 is able to lessen FSGS pathology, such as glomerular sclerosis via interaction with the complement pathways. To investigate this, immunohistochemistry (IHC) was used to semi-quantitatively assess complement protein deposition in the kidneys of the Adriamycin (ADR)-induced FSGS mouse model at 1, 3, and 7-day time points post-ZSJ-0228, dexamethasone and saline vehicle treatment. We have found that the treatment lessens complement protein deposition from both the alternate and classical pathway in the kidneys of diseased mice. These exciting new data shed light on the potential novel pharmacology of ZSJ-0228 and support its further development as a promising drug candidate for the improved clinical management of FSGS.

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Available for download on Wednesday, April 22, 2026

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