Immune dysregulation - Regeneration and biology of the human kidney

Abstract

Kidney diseases can arise from immune dysregulation. One arm of this thesis revealed the relation between common variable immunodeficiency (CVID) or coeliac disease (CD) and immune-mediated renal diseases (IMRDs), the latter deriving from either renal tubules or glomeruli. Proximal tubular cells (PTCs) play important roles in tubules repair and injury progression. The glomerular podocyte is the target cell in many glomerular diseases. Therefore, we sought to elucidate the signature of SOX9, a transcription factor potentially involved in repair of human tubules, and identify novel proteins in human podocytes. Adopting cox regressions, we found that people with CVID (Paper I) were at increased risk to develop chronic nephritic syndrome (CNS), chronic tubule-interstitial nephritis, nephrotic syndrome (NS), Sjögren syndrome (SS) and unspecific nephritis-nephropathy. Following a CD diagnosis (Paper II), the risk of acute nephritic syndrome, CNS, NS, lupus, SS and granulomatosis was lower in CD patients than unrecognized CD patients. If a CD diagnosis was given at earlier age in life, patients had less risk to develop NS and SS. In Paper III, we knocked down SOX9 in human PTCs by means of siRNA. We opposed these cells’ bulk RNA levels to control PTCs and identified LBR, HMGA2, and HIPK3 as target genes of SOX9, with potential regeneration capacities of renal tubules following injury. Moreover, our model of tubular necrosis showed that SOX9+ cells increased in number after reoxygenation, likely to support tissue repair. In Paper IV, using publicly available data and own staining of kidney sections, we identified ARMH4 and WIPF3 as novel proteins expressed in podocytes. Initial mechanistic studies revealed that increase of ARMH4 in mature podocytes reduced the levels of IL1B and IL8; as overexpression of WIPF3 by adenoviral transfection increased the protein level of N-WASP, likely to promote stabilization of the podocyte cytoskeleton. Here, we report the association between CVID and IMRDs. We also show that CD people have a lower risk to develop IMRDs if they receive a diagnosis of CD earlier in life, and that SOX9, and ARMH4 and WIPF3 are important proteins involved in PTCs repair and stabilization of podocytes respectively. Our data may improve management of patients with CVID and CD as well as promote the development of novel therapeutics for nephrotic patients.