No abstract

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4(+) T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (T(H)2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished T(H)2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10(+) and CD206(+) CD11b(high) cells, at 7 d after surgery. We evaluated the role of a T(H)2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and T(H)1:T(H)2 balance, as T(H)2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

Focal and segmental glomerulosclerosis (FSGS) is one of the most important causes of end-stage renal failure. The bradykinin B1 receptor has been associated with tissue inflammation and renal fibrosis. To test for a role of the bradykinin B1 receptor in podocyte injury, we pharmacologically modulated its activity at different time points in an adriamycin-induced mouse model of FSGS. Estimated albuminuria and urinary protein to creatinine ratios correlated with podocytopathy. Adriamycin injection led to loss of body weight, proteinuria, and upregulation of B1 receptor mRNA. Early treatment with a B1 antagonist reduced albuminuria and glomerulosclerosis, and inhibited the adriamycin-induced downregulation of podocin, nephrin, and α-actinin-4 expression. Moreover, delayed treatment with antagonist also induced podocyte protection. Conversely, a B1 agonist aggravated renal dysfunction and even further suppressed the levels of podocyte-related molecules. Thus, we propose that kinin has a crucial role in the pathogenesis of FSGS operating through bradykinin B1 receptor signaling.

Mesenchymal stem cell (MSC) therapy is a promising new therapy for kidney diseases. Many authors have been demonstrated that the MSC treatment leads to N improvement of the renal function in acute damaged models. However, the way it works still remains elusive. Purpose: To evaluate whether the renal protection provided by MSC administration seen in acute and chronic renal remnant damaged models involves modulation of the inflammation. Methods: MSC were attained from bone marrow of male Wistar rats. Female Wistar were subjected to ischemia-reperfusion damage by clamping renal pedicles for 1 hour. After a 6h reperfusion, 2.105 MSC were administrated i.v. in the chronic model. The nephrectomy models 5/6 were treated with 1.106 MSC administered i.v. after two weeks. Results: After a 24h reperfusion, MSC-treated animals presented a significant improvement of the renal function associated to decreased levels of IL-1β, IL-6 and TNF-α gene expression. Interestingly, the IL-4 mRNA expression increased in parallel. Furthermore, a higher expression of PCNA and an increase in the Bcl2/Bad ratio were seen in kidney tissues of MSC-treated animals. In the remnant model, this modulation in the cytokine pattern was sustained, despite a lack of amelioration of the renal dysfunction. Moreover, the expressions of TGF-β, MMP-9, TIMP-1 and Smad7 were not altered, although PAI-1 was significantly decreased. Conclusion: MSC therapy can indeed modulate the inflammatory response following acute and chronic renal injuries, accelerating the tubular repair; however, long-term outcomes seem not to be halted by this therapy.