Chapter 7 122 Patients with proteinuria can suffer from a myriad of diseases that cause protein to pass the glomerular filtration barrier and being insufficiently reabsorbed by the proximal tubule apparatus. These diseases include those that are histopathologically characterized by scarring and fibrosis of glomeruli, such as both primary and secondary focal segmental glomerulosclerosis, and diabetic nephropathy. Other types of diseases leading to proteinuria could be classified as auto-immune mediated, such as lupus nephritis and membraneous nephropathy. Moreover, many monogenetic diseases that cause proteinuria have been identified. Most of these display either a podocytopathy or a defect in tubular reabsorption. Although the underlying pathophysiological mechanisms differ between all of these diseases, they can share some elements in their respective pathways leading to proteinuria. As proteinuria is an independent risk factor for the progression of renal disease, cardiovascular morbidity, and overall mortality, treatments attenuating or relieving proteinuria are needed. Current treatment is mainly focused on the underlying disease and consists of reducing glomerular filtration pressure through inhibition of the renin-angiotensin-aldosterone system and, depending on whether an auto-immune or auto-inflammatory disease is involved, the addition of immunosuppressive drugs such as corticosteroids. Elucidating the pathways leading to proteinuria is required to identify novel potential therapeutic targets for the treatment of proteinuria. Historically, the main constituents of the glomerular filtration barrier were identified through analysis of hereditary proteinuria syndromes, as also reviewed by Tryggvason et al.(16) For example, the slit diaphragm proteins of Nephrin (NPHS1) and Podocin (NPHS2), glomerular basement membrane protein Laminin (LAMB2), and transcription factors that influence podocyte gene expression (WT1 and ACTN4) were all identified by investigation of monogenetic proteinuric diseases. As eloquently said by Iain Drummond: ‘unravelling the molecular pathogenesis of human disease presents many experimental challenges, not the least of which is that experiments on humans are generally frowned upon.(105)’ Although experimentation on animals is also increasingly frowned upon and must rightfully adhere to rigorous ethical standards, it is currently still an indispensable element of pathophysiological research. In this thesis, a combination of cell culture, experimental animal models, histopathological examination of human tissue, and a patient cohort investigation were all employed to investigate pathways leading to proteinuria.
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