The Huang Research Laboratory studies the pathophysiological role of renin-angiotensin-aldosterone system (RASS), transforming growth factor beta (TGFß) and plasminogen activator inhibitor (PAI-1) in the development and progression of renal fibrosis and potential novel strategies for treatment.
One of our major areas of focus is understanding the receptor-mediated prorenin/renin’s action in renal fibrosis. Although pharmacological blockers of the renin-angiotensin system are clearly effective in many renal and cardiovascular diseases, their effectiveness is limited, and exciting novel therapeutic avenues are likely to open through research on receptor-mediated renin and prorenin actions. We have demonstrated the receptor-binding site of renin is distinct from the enzymatic active site on the surface of renin and renin has receptor-mediated profibrotic effects independent of Ang II’s generation and action. We keep our effort to further identify the receptor-binding site on the human renin structure and to elucidate the molecular basis of renin’s dual pathophysiological actions that are both Ang II-dependent and Ang II-independent, as a prerequisite of the development of therapeutic agents blocking renin activity and binding in patients.
The role of prorenin in disease is also an exciting new area for us. Elevated plasma prorenin levels are commonly found in diabetic patients and it has been known for more than 20 years that prorenin levels correlate with microvascular disease including diabetic nephropathy. Neither the cause for elevated prorenin levels nor their role in disease, if any, is known. The work on receptor-mediated activation and profibrotic action of prorenin is potentially important line of investigation, particularly in the development of diabetic nephropathy. We generated an inducible prorenin transgenic rat model and demonstrated that high levels of circulating prorenin cause hypertension and renal and cardiac fibrosis. We keep our effort to generate noncleavable prorenin and enzymatic site-mutant prorenin transgenic rat models to further explore the potential roles and mechanisms of elevated prorenin in the development of hypertension, cardiovascular and kidney disease.We investigate the role of PAI-1 in renal fibrosis. These studies revealed that PAI-1’s ability to inhibit plasmin-dependent extracellular matrix turnover, stimulate infiltration of macrophages and myofibroblasts and signal directly to regulate TGFß expression and injury podocyte, provides possible mechanistic pathways involved in the progression of chronic kidney disease. Our laboratory also studies the non-viral strategies for cell-specific delivery of pathway interactors and molecular probes to diseased kidneys. These studies involve combining siRNA or miRNA with nanobiotechnology to develop a self-assembled nanovector system for gene delivery specifically to glomerular cells.