Role of tubular scattered cells of the kidney in disease and regeneration

Abstract: With well over 700 000 deaths every year worldwide, kidney disease constitutes an immense health problem for patients and society. The total global number of people with kidney disease regardless of severity amounts to a staggering 600 000 000. Not surprisingly, the total health care expenditure associated with kidney disease is second to no other costs, including oncology/cancer. If acute or chronic kidney disease is allowed to progress they may eventually lead to end-stage renal disease. This is unfortunately not an unusual development, since specific treatments for renal disease are virtually none, and current treatments mostly focus on symptoms rather than specifically altering disease progression. The end-stage renal disease is a lethal condition if renal replacement therapy is not amenable in the form of either dialysis or more seldom renal transplantation. Obviously, kidney injury only causes clinically relevant organ damage if the regenerative capacity of the kidney is overwhelmed. Surprisingly the basis for and regulation of kidney regeneration is still not unequivocally established. This is why it is so important to understand the processes behind kidney injury and regeneration.This thesis focuses on the cellular basis for kidney regeneration by investigating the so-called tubular scattered cells (TSCs). These are of central importance for renal injury and regeneration. Whether these cells are stem or progenitor cells or represent cellular reactions to injury is an unsettled issue, despite the intense investigation. First, we established a novel protocol based on fluorescence activated sell sorting (FACS) for rare cell isolatation, allowing us to isolate good quality RNA from cell suspensions after fixation, permeabilization, and intracellular antibody labelling.Next, we focused on mechanistic aspects of the kidney injury and regeneration by studying the transcription factor MKL1. It was shown to control proximal tubular cell expression of caveolin-1, a protein not present in healthy kidney but highly expressed post-renal injury.In the third paper, we investigated the carrier protein polymeric immunoglobulin receptor (pIgR). In normal kidney, we showed this protein to be expressed by TSCs and expression increases significantly after kidney injury and we postulate that this serves to protect the kidney from, among others, ascending bacterial infections by facilitating excretion of IgA into the urine.Next, we analyzed the expression pattern of the transcription factor SOX9 in a normal and diseased kidney. We and others have found SOX9 to be associated with TSCs. We show that SOX9 expression is increased in injured kidney tissue and that the cellular expression is modulated by chemokines secreted from secondary inflammatory infiltrates attracted by tubular injury.Last, we investigated another aspect of TSC pathology. We suggest that papillary renal cell carcinoma (pRCC) is derived from TSCs and that pRCC might use regenerative programs associated with TSCs. We studied the most characteristic feature of the pRCC tumor, which is the presence of foamy macrophages in the papillary fronds. We identified a set of cytokines with the capacity to attract monocytes into the tumor tissue and convert these into M2 phenotype foam cells resulting in the characteristic histology.