Tubular cell-enriched subpopulation of primary renal cells improves survival and augments kidney function in rodent model of chronic kidney disease

Abstract

. Tubular cell-enriched subpopulation of primary renal cells improves survival and augments kidney function in rodent model of chronic kidney disease. Am J Physiol Renal Physiol 299: F1026 -F1039, 2010. First published September 8, 2010 doi:10.1152/ajprenal.00221.2010.-Established chronic kidney disease (CKD) may be identified by severely impaired renal filtration that ultimately leads to the need for dialysis or kidney transplant. Dialysis addresses only some of the sequelae of CKD, and a significant gap persists between patients needing transplant and available organs, providing impetus for development of new CKD treatment modalities. Some postulate that CKD develops from a progressive imbalance between tissue damage and the kidney's intrinsic repair and regeneration processes. In this study we evaluated the effect of kidney cells, delivered orthotopically by intraparenchymal injection to rodents 4 -7 wk after CKD was established by two-step 5/6 renal mass reduction (NX), on the regeneration of kidney function and architecture as assessed by physiological, tissue, and molecular markers. A proof of concept for the model, cell delivery, and systemic effect was demonstrated with a heterogeneous population of renal cells (UNFX) that contained cells from all major compartments of the kidney. Tubular cells are known contributors to kidney regeneration in situ following acute injury. Initially tested as a control, a tubular cellenriched subpopulation of UNFX (B2) surprisingly outperformed UNFX. Two independent studies (3 and 6 mo in duration) with B2 confirmed that B2 significantly extended survival and improved renal filtration (serum creatinine and blood urea nitrogen). The specificity of B2 effects was verified by direct comparison to cell-free vehicle controls and an equivalent dose of non-B2 cells. Quantitative histological evaluation of kidneys at 6 mo after treatment confirmed that B2 treatment reduced severity of kidney tissue pathology. Treatmentassociated reduction of transforming growth factor (TGF)-␤1, plasminogen activator inhibitor (PAI)-1, and fibronectin (FN) provided evidence that B2 cells attenuated canonical pathways of profibrotic extracellular matrix production. regeneration; stabilization CHRONIC KIDNEY DISEASE (CKD) affects more than 19 million people in the U.S. and frequently develops as a consequence of chronic obesity, diabetes, and/or hypertension (42). Patients in stage 4 -5 CKD receive dialysis and a complex drug regimen, and the number of kidneys available for transplant is vastly insufficient to meet the need (30). New treatments that delay or reduce dialysis dependence are needed to fill this void.Kidney tissue is composed of Ͼ20 specialized cell types structurally organized into morphologically and functionally distinct compartments that act in concert to filter blood, produce urine, and regulate endocrine function and acid-base and electrolyte balance. Cell-cell interactions are critical to kidney function and are at least partially dependent on spatial and architectural relations...

Association of PAX2 with Cell Apoptosis in Unilateral Ureteral Obstruction Rats

“…51,52 The increased ROS might upregulate the gene expression of PAX2, 49,50 which regulated the expression of TGF-β1. 53,54 The disorder of TGF-β1 might induce the expressions of α-SMA, Col-IV, and FN, [21][22][23] and the increased TGF-β1 upregulated the expression of caspase-3. [55][56][57] The overexpression of caspase-3 was associated with cell apoptosis.…”

“…19,20 TGF-β1 is known to be one of the major mediators which leads to RIF by inducing the production of α-SMA and ECM (Col-IV and FN) in the renal interstitium. [21][22][23] So, TGF-β1, α-SMA, Col-IV, and FN are the important indicators for evaluating the grade of RIF lesion and the progression of RIF. Caspase-3 is a pivotal effector of the apoptosis machinery 24 and its activity is associated with cell apoptosis.…”

Tissue Engineering of Tubular and Solid Organs: An Industry Perspective

“…At Tengion, development of the Neo-Kidney Augment (NKA TM ), a cell/biomaterial composite for renal tissue engineering, has focused on step-wise identification of bioactive cellular components and biomaterials amenable to implantation within renal parenchyma. To this end, we have leveraged principles discussed throughout this chapter, identifying lineage committed, primary renal cell populations as therapeutically bioactive agents capable of mediating functional rescue of aspects of disease phenotype within small animal clinical models of chronic kidney disease (Kelley et al, 2010;Presnell et al, 2010). Similarly, our evaluation of biomaterials compatible with renal parenchyma has led us towards application of gelatin hydrogels as the best tolerated biomaterial scaffold for renal tissue engineering (Basu et al, 2011b).…”

Molecular Characterization of the Regenerative Response Induced by Intrarenal Transplantation of Selected Renal Cells in a Rodent Model of Chronic Kidney Disease

“…Such tubular epithelial-enriched cell populations may be selected from a primary kidney cell isolate prepared from the medulla, cortex and corticomedullary junction compartments of kidneys based on differential buoyant density centrifugation. These cell populations have been phenotypically characterized in detail at the morphological, transcriptomic and immunohistochemical levels [Kelley et al, 2010a[Kelley et al, , 2010bPresnell et al, 2010]. Briefly, these cell populations are principally composed of E-cadherin+, Pan-cadherin+, cytokeratin 8/18/19+, ␥ -glutamyl transpeptidase+ cells and oxygen-responsive erythropoietin+ subpopulations [Presnell et al, 2010].…”

“…Briefly, these cell populations are principally composed of E-cadherin+, Pan-cadherin+, cytokeratin 8/18/19+, ␥ -glutamyl transpeptidase+ cells and oxygen-responsive erythropoietin+ subpopulations [Presnell et al, 2010]. Taken together, these selected primary kidney cell isolates are described as being 'therapeutically bioactive' because orthotopic transplantation is associated with increased survival and enhanced renal functionality upon intrarenal administration to rodents with CKD secondary to 2-step 5/6 Nx [Kelley et al, 2010a[Kelley et al, , 2010bPresnell et al, 2010]. Therefore, such therapeutically bioactive cell populations may be valuable components of products developed to augment kidney function in patients with CKD.…”