Acute kidney injury is followed by regeneration of damaged renal tubular epithelial cells. The purpose of this study was to test the hypothesis that renal stem cells exist in the adult kidney and participate in the repair process. A unique population of cells that behave in a manner that is consistent with a renal stem cell were isolated from rat kidneys and were termed multipotent renal progenitor cells (MRPC). Features of these cells include spindle-shaped morphology; self-renewal for >200 population doublings without evidence for senescence; normal karyotype and DNA analysis; and expression of vimentin, CD90 (thy1.1), Pax-2, and Oct4 but not cytokeratin, MHC class I or II, or other markers of more differentiated cells. MRPC exhibit plasticity that is demonstrated by the ability of the cells to be induced to express endothelial, hepatocyte, and neural markers by reverse transcriptase-PCR and immunohistochemistry. The cells can differentiate into renal tubules when injected under the capsule of an uninjured kidney or intra-arterially after renal ischemia-reperfusion injury. Oct4 expression was seen in some tubular cells in the adult kidney, suggesting these cells may be candidate renal stem cells. It is proposed that MRPC participate in the regenerative response of the kidney to acute injury.

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Apoliprotein J (apoJ)/clusterin has attracted considerable interest based on its inducibility in multiple injury processes and accumulation at sites of remodeling, regression, and degeneration. We therefore sought to investigate apoJ/clusterin's role in kidney aging, as this may reveal the accumulated effects of diminished protection. Aging mice deficient in apoJ/clusterin developed a progressive glomerulopathy characterized by the deposition of immune complexes in the mesangium. Up to 75% of glomeruli in apoJ/clusterin-deficient mice exhibited moderate to severe mesangial lesions by 21 months of age. Wild-type and hemizygous mice exhibited little or no glomerular pathology. In the apoJ/clusterin-deficient mice, immune complexes of immunoglobulin G (IgG), IgM, IgA, and in some cases C1q, C3, and C9 were detectable as early as 4 weeks of age. Electron microscopy revealed the accumulation of electron-dense material in the mesangial matrix and age-dependent formation of intramesangial tubulo-fibrillary structures. Even the most extensively damaged glomeruli showed no evidence of inflammation or necrosis. In young apoJ/clusterin-deficient animals, the development of immune complex lesions was accelerated by unilateral nephrectomy-induced hyperfiltration. Injected immune complexes localized to the mesangium of apoJ/clusterin-deficient but not wild-type mice. These results establish a protective role of apoJ/clusterin against chronic glomerular kidney disease and support the hypothesis that apoJ/clusterin modifies immune complex metabolism and disposal.Apolipoprotein J (apoJ)/clusterin is a circulating glycoprotein constitutively expressed by diverse epithelial cells. The protein is induced in injured organs in various disease states, such as Alzheimer's disease, atherosclerosis, myocardial infarction, and multiple forms of acute and chronic renal disease (20,25). Proposed functions for apoJ/clusterin include lipid transport, complement defense, regulation of apoptosis, membrane protection, and promotion of cell-cell interactions (25). ApoJ/ clusterin can bind a large number of macromolecules implicated in disease initiation and progression, including immunoglobulins and complement components. Recently clusterin has been demonstrated to function as a molecular chaperone, preventing denatured protein precipitation through binding to exposed hydrophobic regions and improving high-molecularweight complex solubility (6).The structure of apoJ/clusterin has not provided much insight into function. Mammalian apoJ/clusterins are approximately 80-kDa heterodimers (9, 16) consisting of two 40-kDa chains joined by a unique five-disulfide-bond motif (10). The protein has limited homology to other proteins and lacks clear functional motifs (9). It does contain three putative amphipathic ␣-helical regions, which could allow it to interact with lipids and hydrophobic regions of other proteins (6).We have recently shown that apoJ/clusterin-deficient mice exhibit enhanced inflammatory severity and sequelae in an autoimmune myocarditis...

This proof-of-principle clinical observation demonstrates that extrarenal cells can participate in the regenerative response following ATN. These findings provide rationale for the cellular therapy of acute renal failure.

The function of clusterin, a heterodimeric glycoprotein markedly induced in renal and other organ injuries, is un-clear. Since renal injury is accompanied by alterations in cell attachment, it is possible that clusterin functions to promote cell-cell and cell-substratum interactions. In this study, a single cell suspension of renal epithelial (LLC-PK1) cells was treated with purified human clusterin, resulting in timeand dose-dependent cell aggregation. Electron microscopy of the cell aggregates demonstrated cell junction and lumen formation. To determine the effect of clusterin on cell adhesion, tissue culture plates were coated with clusterin, fibronectin, PBS, or albumin. Clusterin and fibronectin promoted cell adhesion to the same extent. The adhesion to clusterin was dose dependent and specific, as a monoclonal antibody against clusterin inhibited cell adhesion to clusterin but not fibronectin. Perturbations of the cytoskeleton may underlie the alterations in cell attachment which occur in renal injury. Induction of clusterin mRNA was seen after disruption of both microtubules and microfilaments and after inhibition of cell-substratum interactions. In conclusion, clusterin is a potent renal epithelial cell aggregation and adhesion molecule. We speculate that clusterin functions to promote cell-cell and cell-substratum interactions which are perturbed in the setting of renal injury, thereby preserving the integrity of the renal epithelial barrier. (J. Clin. Invest. 1995Invest. . 96:2646Invest. -2653