Chronic kidney disease (CKD) is considered an important health issue worldwide. The renin–angiotensin–aldosterone system (RAAS) blockade through the administration of angiotensin II receptor blockers, such as Losartan (LOS), has been considered the best strategy for CKD treatment for decades. However, this approach promotes only partial detention of CKD progression and cannot reverse renal damage. The aim of the present study was to investigate whether the therapeutic administration of extracellular vesicles (EVs) derived from adipose stem cells (ASCs), associated to LOS treatment, would promote additional renoprotection in rats underwent the 5/6 renal ablation CKD model. ASC-derived EV were administered locally, in the renal subcapsular area, 15 days after CKD induction, when LOS therapy also began. Animals were followed for additional 15 days and our results demonstrated that subcapsular injection of ASC-derived EV associated with LOS significantly reduced glomerulosclerosis, renal interstitial infiltration by myofibroblasts, and macrophages in the 5/6 CKD model. Additionally, LOS + EV abrogated systemic hypertension, proteinuria, and albuminuria, and stimulated local gene overexpression of the endogenous anti-inflammatory Il-4. Although more studies are still required to establish the best EV dose and administration route, these findings point to therapy with ASC-derived EV as a potential adjuvant in CKD treatment

Almost 10% of the global population suffers from chronic kidney disease (CKD). The inexistence of a therapeutic to restore renal function motivates the scientific community to search for new treatments. The 5/6 nephrectomy (Nx) rat model is widely used to mimic human CKD, but the impact of strain-specific responses on disease progression remains unclear. Here, we aimed to compare CKD development in Wistar, Lewis, and Fischer rats submitted to the Nx model. In summary, even submitted to the same surgical procedure, the three studied rat strains presented distinct patterns of CKD progression: Wistar rats exhibited faster and sustained renal function loss, with exuberant hypertension, proteinuria, and renal inflammation, being considered as excellent models to study rapidly progressive human nephropathy. Lewis animals, in turn, presented mild low-progressive CKD, which make this rat strain especially useful to simulate intermediate degrees of human CKD and to develop long-term tests. Finally, Fischer rats submitted to Nx did not even develop hypertension, proteinuria, or glomerular damage within 30 days. Moreover, compared to Wistar rats, both Lewis and Fischer animals have a relatively higher basal number of nephrons and a lower number of whole blood leukocytes, which may have contributed to the renoprotection exhibited by these rat strains.

Chronic kidney disease (CKD) is considered an important health issue worldwide. The ren-in-angiotensin-aldosterone system (RAAS) blockade through the administration of angiotensin II receptor blockers, such as Losartan (LOS), have been considered the best strategy for CKD treatment for decades. However, this approach promotes only partial detention of CKD pro-gression and cannot reverse renal damage. The aim of the present study was to investigate whether the therapeutic administration of extracellular vesicles (EV) derived from adipose stem cells (ASC), associated to LOS treatment, would promote additional renoprotection in rats underwent the 5/6 renal ablation CKD model. ASC-derived EV were administered locally, in the renal subcapsular area, 15 days after CKD induction, when LOS therapy also began. Animals were followed for additional 15 days and our results demonstrated that subcapsular injection of ASC-derived EV associated with LOS, significantly reduced glomerulosclerosis, renal interstitial infiltration by myofibroblasts and macrophages in the 5/6 CKD model. Additionally, LOS+EV abrogated sys-temic hypertension, proteinuria and albuminuria, and stimulated local overexpression of the endogenous anti-inflammatory IL-4. Although more studies are still required to establish the best EV dose and administration route, these findings point to therapy with ASC-derived EV as a po-tential adjuvant in CKD treatment.

Almost 10% of the global population suffers from chronic kidney disease (CKD), a severe, progressive and irreversible condition that usually leads to the necessity of life-sustaining renal replacement therapy. The inexistence of a therapeutic intervention able to restore renal function loss motivates the scientific community to develop experimental and preclinical studies in search for new drugs and treatments. Most of these studies require animal models of CKD in order to resemble human nephropathy and human pathophysiological responses, and one of the main employed animals for this purpose is the rat (Rattus norvegicus). Among the variety of available rat CKD models described in the literature, the sub-total nephrectomy model, achieved through the 5/6 renal ablation, stands out, since it better mimics human CKD development and progression. However, there are still no consensus on the most appropriate rat strain for this purpose. The aim of this study was to compare the development and severity of the nephropathy associated to the 5/6 renal ablation model in Wistar, Lewis and Fischer rats. In summary, we observed that, even submitted to the very same surgical procedure of renal mass reduction, the 3 studies rat strains presented completely distinct patterns of CKD progression: Wistar rats exhibited faster, rapidly-progressive and sustained renal function loss, with exuberant hypertension, proteinuria and renal inflammation, and can be considered as excellent animal models to study rapidly progressive, severe human nephropathy and to develop quick tests on new therapies and drugs. Lewis animals, in turn, presented mild and low-progressive CKD, which make this rat strain especially useful to simulate intermediate degrees of human CKD and to develop long-term drug tests. Finally, Fischer rats submitted to the same 5/6 renal ablation model, not even developed hypertension nor proteinuria or structural glomerular damage. We also demonstrated that, compared to Wistar rats, both Lewis and, especially Fischer control rats have a relative higher basal number of nephrons, which may have consistently contributed to the observer renoprotection exhibited by this last rat strain.