Abstract
Podocytes are specialized cells with a limited capacity for cell division that do not regenerate in response to injury and loss. Insults that compromise the integrity of podocytes promote proteinuria and progressive renal disease. The aim of this study was to evaluate the potential renoprotective and regenerative effects of mesenchymal stromal cells (mSC) in a severe form of the podocyte injury model induced by intraperitoneal administration of puromycin, aggravated by unilateral nephrectomy. Bone derived mSC were isolated and characterized according to flow cytometry analyses and to their capacity to differentiate into mesenchymal lineages. Wistar rats were divided into three groups: Control, PAN, and PAN+ mSC, consisting of PAN rats treated with 2 × 105 mSC. PAN rats developed heavy proteinuria, hypertension, glomerulosclerosis and significant effacement of the foot process. After 60 days, PAN rats treated with mSC presented a significant amelioration of all these abnormalities. In addition, mSC treatment recovered WT1 expression, improved nephrin, podocin, synaptopodin, podocalyxin, and VEGF expression, and downregulated proinflammatory Th1 cytokines in the kidney with a shift towards regulatory Th2 cytokines. In conclusion, mSC administration induced protection of podocytes in this experimental PAN model, providing new perspectives for the treatment of renal diseases associated with podocyte damage.
Highlights
Podocytopathies are the most common group of glomerular diseases in which proteinuria is attributed to damage or dysfunction of podocytes[1]
Treatment with mesenchymal stromal cells (mSC) in puromycin aminonucleoside nephrosis (PAN) animals had no effect on body weight (Table 2) or renal function, as analyzed based on the Blood urea nitrogen (BUN) and serum creatinine levels (Supplementary Table 1)
We evaluated the potential renoprotective effects of mSC in the podocyte injury model induced by PAN in rats
Summary
Podocytopathies are the most common group of glomerular diseases in which proteinuria is attributed to damage or dysfunction of podocytes[1]. To induce more pronounced glomerular lesions, unilateral nephrectomy (UniNx) can be associated in this model[8] Owing to their terminal differentiation nature, podocytes have a limited capacity to undergo cell division and, do not regenerate in response to injury, depletion or aging[9,10]. Excessive podocyte loss predisposes to glomerular disorders and subsequent chronic kidney disease (CKD). In the present study, we developed a severe podocyte injury model in Wistar rats, characterized by cumulative doses of the puromycin aminonucleoside and UniNx to mimic FSGS podocytopathy in humans, and we analyzed the possible renoprotective effects of mSC therapy on clinical and morphological parameters, as well as the possible modulatory effects of cytokines and vascular endothelial factor (VEGF)
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