Acute Rejection Modulates Gene Expression in the Collecting Duct

Abstract

Kidney transplantation, especially when associated with acute rejection, leads to changes in the expression of many genes, including those encoding solute transporters and water channels. In a rat model of acute rejection after allogeneic renal transplantation, impaired renal function, increased urine volume, and increased fractional excretion of sodium were observed. Gene array analysis revealed that these findings were associated with significant downregulation of water channels (aquaporin-1, -2, -3, and -4) and transporters of sodium, glucose, urea, and other solutes. In addition, changes in expression of various receptors, kinases, and phosphatases that modulate the expression or activity of renal transport systems were observed. Syngeneic transplantation or treatment with cyclosporine A following allogeneic transplantation did not impair graft function but did lead to the downregulation of aquaporin-1, -3, and -4 and several solute transporters. However, expression of aquaporin-2 and the epithelial sodium channel did not change, suggesting that the downregulation of these transporters following allogeneic transplantation is rejection-dependent. In conclusion, changes in gene expression may explain the impaired handling of solute and water after allogeneic transplantation, especially during acute rejection. Treatment with cyclosporine A improves the regulation of solute and water by preventing the downregulation of aquaporin-2 and epithelial sodium channel, even though many other transporter genes remain downregulated. Renal transplantation (TX) in humans is often accompanied by increased transport capacities of the graft and disturbances in salt and water homeostasis. 1-3 Half-life of grafts with normal function after TX is 11.5 yr compared with 7.2 yr for those with impaired renal function. 4 A better understanding of the underlying cellular and molecular mechanisms leading to such changes may help to increase longterm graft survival.Previously, using an allogeneic rat renal TX (aTX) model, we have demonstrated acute changes in expression and function of several transporters and receptors after aTX. 5,6 For example, the expression of Na ϩ /H ϩ -exchanger-3 (NHE3), aquaporin-2 (AQP2), and the epithelial Na ϩ channel (ENaC) were downregulated at the protein and mRNA level. Major transporters for water and Na ϩ reabsorption in the collecting duct (CD) are ENaC and AQP2. 7 The expression and activity of AQP2 are regulated by the antidiuretic hormone (vasopressin, AVP) via the G-protein coupled AVP-2 receptor (V2R). 8 The binding of AVP to the V2R leads to the activation of the G-protein Gs, followed by activation of adenylate cyclase (AC), increased cyclic adenosine monophosphate (cAMP) levels, activation of protein kinase A (PKA), and finally phosphorylation of AQP2 9 and translocation to the

Potential of Noninvasive Serial Assessment of Acute Renal Allograft Rejection by 18F-FDG PET to Monitor Treatment Efficiency

“…Grafts were recovered on postoperative day 1, 4, or 7 after transplantation. The chosen aTX model leads to histologic and functional changes typical of acute rejection (19,20). Syngeneically transplanted (sTX) rats (Lewis-brown Norway to Lewis-brown Norway) and aTX rats treated with cyclosporine A (CSA, 5 mg/kg of body weight/d intraperitoneally) since transplantation (postoperative day 0) without allograft rejection served as controls.…”

Different effects of CsA and FK506 on aquaporin-2 abundance in rat primary cultured collecting duct cells

“…Studies in this field show that AQP2 abundance-along with several other key transporters in the distal nephron-is decreased in animal models of acute graft rejection [44]. These effects are consistent with tubular damage induced by the stimulated immune system and are known to be ameliorated or even reversed by calcineurin inhibitor treatment [8,9].…”

Precision Sub-phenotyping of Histologically Stable Kidney Transplants by a Composite Molecular and Cellular Instability Score

“…In this study we identified discrepancies in the current histological recognition of stable allografts and demonstrated a new Instability Score (or InstaScore), a linear combination of selected features based on the input from tissue gene expression and inferred cell type biopsy molecular data modeled on AR biology, that provides precise (sub-)phenotyping and early recognition of molecular and cellular rejection of otherwise functionally and histologically stable allografts on protocol biopsies. Unlike other published studies by others [61][62][63][64][65] and our group [2,54,66,67] that have only studied gene expression transcriptional perturbation in AR, this is the first development and application of a combined genes and cell types into Instability Score in tissue that can rapidly reclassify samples into molecularly and even more importantly, functionally relevant, diverse groups: those most similar to the normal kidneys (hSTA/mSTA) and those most similar to the rejected kidneys (hSTA/mAR).…”