Mesenchymal stem cell therapy for halting the progression of acute and chronic kidney injury and in vivo modulate kidney-derived c-Kit stem cells

Abstract

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) in the world, affecting thousands of people worldwide, regardless of gender, age, ethnicity, or socio-demographic condition. DM leads to chronic macro- and micro-angiopathic DM-related complications and is also the major cause of blindness and amputation. Blockade of the renin-angiotensin-aldosterone system is the most effective measure to delay progression of diabetic nephropathy, although 30-40% of patients progress to CKD. Thus, the study of new therapeutic options that halt the progress of diabetic nephropathy (DN) is necessary to reduce the morbidity and mortality of diabetic patients. These therapeutic options include cell therapy with mesenchymal stem cells (MSCs), modulation of specific stem cells/progenitors of renal tissue, transplantation of fecal microbiota and use of new oral medications and new insulin presentations. The objectives of this study are the understanding of the mechanisms of action of MSCs for the regeneration of mesangial cells grown in hyperglycemic medium containing hydrogen peroxide in vitro. The co-culture of MSCs with mesangial cells submitted to oxidative stress restores mitochondrial quality dynamics in mesangial cells and is mediated by the transfer of mitochondria through nanotubes induced by the Miro-1 protein. Furthermore, since the therapeutic potential of MSCs is well established in preclinical models in rodents submitted to either acute or chronic injury, we will verify if MSCs delay the progression of DN in genetically modified obese mice (knockout for leptin or BTBR ob/ob mice). These mice develop DN similar to humans, including mesangial expansion, mesangiolysis, podocyturia, arteriolar hyalinosis, and tubulo-interstitial fibrosis. In order to confirm these findings, we will evaluate if the genetically modified MSCs containing the growth factors HGF (hepatocyte growth factor) and klotho developed in nanoparticles present greater local therapeutic potential in relation to the antifibrotic and regenerative properties when compared to non-genetically engineered MSC- modified. From the generation of c-KitCre; mTmG; BTBR ob/ob transgenic mice, injected with tamoxifen in certain periods, we will evaluate the role of c-Kit positive cells during the progression of DN and their proliferative and differentiation capacity in several renal compartments, such as tubular, endothelial, glomerular epithelial, including podocytes. We will also evaluate whether the administration of CTMs and stem cells / progenitor c-Kit (combo) has greater regenerative potential than isolated cell infusion.Our work is original since BTBR ob/ob mice have not been used to date for the efficacy analysis of CTMs and for expression analysis of stem cells/progenitor c-Kit in vivo. (AU)