Modifiers of Renal Response to Injury: (with a Focus on CTGF)

The incidence and prevalence of Chronic Kidney Disease is quickly rising in the Western world. CKD is characterized by the deposition of excessive amounts of connective tissue; a process commonly known as fibrosis. Additionally, it has become clear in recent years that, contrary to what was previously thought, Acute Kidney Injury predisposes to CKD development and renal fibrosis later in life. In this Thesis, several modifiers of renal response to injury including renoprotective factors, such as rapamycin, tamoxifen and bone morphogenetic proteins, as well as pro-fibrotic modifiers including aging and Connective Tissue Growth Factor (CTGF) are studied.

The first part of the thesis focuses on the identification of patients at risk, pathological mechanisms and associated therapeutic targets. Chapter 2 describes a histological scoring method capable of predicting development of CKD after renal transplantation. Chapter 3 addresses the predictive value of increased plasma CTGF levels and the occurrence of cardiovascular events (morbidity and mortality). In Chapter 4, the origin of the myofibroblast, the cell type considered largely responsible for renal fibrogenesis, is discussed followed by a section providing therapeutic targeting strategies based upon these origins. Chapters 5 and 6 describe interventional studies aimed at combating CKD by targeted Rapamycin delivery, or Tamoxifen treatment respectively in animal models of renal injury. In Chapter 7, evidence is provided that suggests BMP7 exerts anti-fibrotic effects in a CTGF dependent fashion.

The second part describes research performed in order to 1) unravel the functionality of CTGF during the chronic response to renal injury, and 2) determine the feasibility of targeting CTGF as an interventional strategy. This is ultimately combined with a general discussion linking both the former and the latter parts of this thesis. Chapter 8 provides a general introduction further outlining the functions of CTGF, and reviews experimental work performed regarding CTGF intervention. A section addressing Platelet Derived Growth Factor (PDGF) and Epidermal Growth Factor (EGF), two alternative driving forces in CKD progression, complements the former. Chapter 9 describes how 50% CTGF reduction is insufficient to reduce disease progression in severe models of CKD. Chapter 10 shows that CTGF reduction below baseline levels is renoprotective with regards to fibrogenesis even in a severe model of CKD and that CTGF silencing is associated with reduced lymphangiogenesis. Additionally, it is shown that CTGF actively increases expression but halts biological functionality of VEGF-C, a major driving force of lymphangiogenesis. In Chapter 11, we identify a shift in CTGF/BMP6 ratio as a potential driving force underlying an age related differential response to kidney injury. Finally, Chapter 12 is an overarching discussion of the novel insights gained in this thesis including opportunities for implementation and follow-up.