This dissertation, "The Role of Angiotensin II and Angiotensin Receptors in the Pathogenesis of IgA Nephropathy" by Yuk-yee, Chan, 陳玉儀, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled The role of angiotensin II and angiotensin receptors in the pathogenesis of IgA nephropathy Submitted by Chan Yuk Yee for the degree of Doctor of Philosophy at The University of Hong Kong in May 2006 IgA nephropathy (IgAN), characterized by mesangial IgA deposition, runs a highly variable clinical course with frequent involvement of tubulointerstitial damage. In IgAN, renal progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions. A subgroup of IgAN with severe tubulointerstitial damage is often associated with a more rapid progression to end-stage renal failure. Mesangial IgA deposition induces local release of cytokines, complement and angiotensin II (Ang II) leading to glomerular inflammation. It remains unclear how mesangial IgA deposition leads to tubulointerstitial injury in IgAN. Histologically, IgA deposits are rarely detected in renal interstitium in IgAN. Whether IgA in IgAN exerts any pathological effects on renal tubules remains unresolved. We hypothesize that mediators released from human mesangial cells (HMC) triggered by IgA deposition leads to activation of tubular epithelial cells. Experimentally, we found that the binding of IgA isolated from patients with IgAN to proximal tubular epithelial cells (PTEC) was less than one-tenth to that of HMC in IgAN and the binding was not mediated through known IgA receptors. When PTEC was cultured with IgA-HMC medium prepared from IgAN patients, there was enhanced proliferation of PTEC and increased synthesis of TNF-α, MIF and sICAM-1. These findings implicate that mediators released from the mesangium after IgA deposition activates renal tubular cells. The glomerulo-tubular cross-talk with mediators released from the mesangium modulates the pathogenesis of tubulointerstitial damage in IgAN. Enhanced renal expression for the renin-angiotensin system (RAS) is detected in IgAN. The RAS has been implicated in the development of progressive renal fibrosis in IgAN. Angiotensin II, a mediator released following mesangial IgA deposition, plays an important role in glomerular hemodynamic adaptation and injury. Both angiotensin II subtype 1 receptor (AT1R) and angiotensin II subtype 2 receptor (AT2R) are expressed in normal and diseased human kidneys. The histological distribution of these receptors supports the notion that they may have physiological role in both normal and diseased human kidneys. Reduced glomerular expression of AT1R was demonstrated in renal biopsies from patients with IgAN. Using cell culture models, we have shown a reduction in mesangial expression of AT1R under acute exposure to IgA, suggesting a regulatory response to high intrarenal Ang II concentration in IgAN. On the other hand, increased tubular expression of AT1R and AT2R was found in IgAN. In vitro cell culture experiment have further demonstrated that the up-regulation of Ang II receptors was not due to the direct effects of IgA but the indirect effect following IgA deposition on HMC. When PTEC was cultured with IgA-HMC medium prepared from IgAN patients, Ang II production was up-regulated leading to inflammation and apoptosis via the AT1R and AT2R respectively. Sequential expression of Ang II receptors determined the injury of PTEC induced by mediators in the IgA-HMC medium prepared from IgAN pat