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Inflammation, a process intimately linked to renal disease, can be defined as a complex network of interactions between renal parenchymal cells and resident immune cells, such as macrophages and dendritic cells, coupled with recruitment of circulating monocytes, lymphocytes, and neutrophils. Once stimulated, these cells activate specialized structures such as Toll-like receptor and Nod-like receptor (NLR). By detecting danger-associated molecules, these receptors can set in motion major innate immunity pathways such as nuclear factor ĸB (NF-ĸB) and NLRP3 inflammasome, causing metabolic reprogramming and phenotype changes of immune and parenchymal cells and triggering the secretion of a number of inflammatory mediators that can cause irreversible tissue damage and functional loss. Growing evidence suggests that this response can be deeply impacted by the crosstalk between the kidneys and other organs, such as the gut. Changes in the composition and/or metabolite production of the gut microbiota can influence inflammation, oxidative stress, and fibrosis, thus offering opportunities to positively manipulate the composition and/or functionality of gut microbiota and, consequentially, ameliorate deleterious consequences of renal diseases. In this review, we summarize the most recent evidence that renal inflammation can be ameliorated by interfering with the gut microbiota through the administration of probiotics, prebiotics, and postbiotics. In addition to these innovative approaches, we address the recent discovery of new targets for drugs long in use in clinical practice. Angiotensin II receptor antagonists, NF-ĸB inhibitors, thiazide diuretics, and antimetabolic drugs can reduce renal macrophage infiltration and slow down the progression of renal disease by mechanisms independent of those usually attributed to these compounds. Allopurinol, an inhibitor of uric acid production, has been shown to decrease renal inflammation by limiting activation of the NLRP3 inflammasome. So far, these protective effects have been shown in experimental studies only. Clinical studies will establish whether these novel strategies can be incorporated into the arsenal of treatments intended to prevent the progression of human disease.

Population studies have shown an association between diabetic nephropathy (DN) and insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene (ACE in humans, Ace in mice). The aim was to evaluate the modulation of Ace copies number and diabetes mellitus (DM) on renal RAS and correlate it with indicators of kidney function. Increased number of copies of the Ace gene, associated with DM, induces renal dysfunction. The susceptibility to the development of DN in 3 copies of animals is associated with an imbalance in activity of RAS enzymes leading to increased synthesis of Ang II and Ang-(1–7). Increased concentration of renal Ang-(1–7) appears to potentiate the deleterious effects triggered by Ang II on kidney structure and function. Results also show increased bradykinin concentration in 3 copies diabetic group. Taken together, results indicate that the deleterious effects described in 3 copies diabetic group are, at least in part, due to a combination of factors not usually described in the literature. Thus, the data presented here show up innovative and contribute to understanding the complex mechanisms involved in the development of DN, in order to optimize the treatment of patients with this complication.

Increasing evidence shows the essential participation of gut microbiota in human health and diseases by shaping local and systemic immunity. Despite an accumulating body of studies showing that chronic kidney disease (CKD) is closely associated with disturbances in the composition of gut microbiota, it remains unclear the importance of gut microbiota in the onset and development of CKD. For the purpose of untangling the role of gut microbiota in CKD, gut microbiota was depleted with a pool of broad-spectrum antibiotics in mice submitted to unilateral ureteral obstruction (UUO). Depletion of gut microbiota significantly decreased levels of proinflammatory cytokines and fibrosis markers, attenuating renal injury. Additionally, to study whether the pathogenic role of gut microbiota is dependent of microbial-host crosstalk, we generated mice lacking Myd88 (myeloid differentiation primary response gene 8) expression in intestinal epithelial cells (IECs) and performed UUO. The absence of Myd88 in IECs prevented a bacterial burden in mesenteric lymph nodes as observed in WT mice after UUO and led to lower expression of proinflammatory cytokines and chemokines, reducing deposition of type I collagen and, ultimately, attenuating renal damage. Therefore, our results suggest that the presence of gut microbiota is crucial for the development of CKD and may be dependent of Myd88 signaling in IECs, which appears to be essential to maturation of immune cells intimately involved in aggravation of inflammatory scenarios.

Tonin, a serine-protease that forms Angiotensin II (AngII) from angiotensinogen, is increased in failing human heart samples. Increased blood pressure (BP) and decreased heart rate (HR) variabilities are associated with higher risk of cardiovascular morbidity. Losartan has been used to reduce hypertension and, therefore, lowers the risk of fatal and non-fatal cardiovascular events. Determination of tonin's impact on BP and HR variabilities as well as the impact of losartan remain questions to be elucidated. Evaluation of cardiovascular autonomic profile in transgenic mice overexpressing the rat tonin enzyme TGM'(rton) and the impact of AT1 receptor blocker, losartan. Male C57BL/6 (WT) and TGM'(rTon) mice were cannulated for recording BP (Windaq, 4 MHz) for 30 min at baseline and 30 min after losartan injection (20 mg/kg). BP and HR variabilities were analyzed in time and frequency domain method. Low-frequency (LF) and high-frequency (HF) components were identified for sympathetic and parasympathetic modulations analysis. Ang I, AngII, and Ang1-7 were quantified by high performance liquid chromatography method. The total enzymatic activity for AngI, AngII, and Ang1-7 formation was evaluated in the heart and plasma by Liquid chromatography mass spectrometry (LC-MS/MS). At the baseline TGM'(rTon) exhibited higher BP, lower cardiac LF, higher cardiac HF, lower LF/HF, and lower alpha index than wild type (WT). After losartan injection, TGM'(rTon) mice presented an additional decrease in cardiac LF and increase in HF in relation to baseline and WT. In the vasculature, losartan caused decreased in BP and LF of systolic BP in WT mice in relation to its baseline. A similar effect was observed in the BP of TGM'(rTon) mice; however, LF of systolic BP increased compared to baseline. Our data also indicates that AT1R receptor signaling has been altered in TGM'(rTon)mice. Interestingly, the dynamics of the renin-angiotensin system kinetics change, favoring production of Ang1-7. Autonomic evaluation of TGM'(rTon) mice indicates an unclear prognosis for diseases that affect the heart. HR variability in TGM'(rTon) mice indicates high risk of morbidity, and sympathetic and parasympathetic modulation indicate low risk of morbidity. The low risk of morbidity could be the biased production of Ang1-7 in the heart and circulation; however, the altered response of AT1R in the TGM'(rTon) remains to be elucidated, as well aswhether that signaling is pro-protection or pro-pathology.

The renin angiotensin system (RAS) has crucial action in the kidney; it is able to modulate intrarenal hemodynamics, glomerular filtration, and fluid and electrolytes homeostasis. Currently, six components of this system mediate their action through receptor(s). Four peptides, Ang II, Ang-(1-7), Ang III and Ang IV; and two enzymes, renin and prorenin through the renin and prorenin receptor, respectively. Angiotensin II (Ang II), the main peptide of RAS, through its type 1 receptor (AT1R) alters intrarenal hemodynamics, glomerular filtration, and fluid and electrolytes homeostasis readjusting blood pressure and body fluid balance. In the later functions, direct action of Ang II on the sodium and water transport was observed and related to diuretic/anti-diuretic and natriuretic/anti-natriuretic action depending on Ang II concentration. Angiotensin-(1-7) also influences the glomerular filtration rate but without changing the blood pressure. This heptapeptide showed biphasic direct action on tubular transport of sodium and water, but there is no consensus which receptor translates its tubular effect. Reports showed that Angiotensin III and Angiotensin IV could present natriuretic action; the pressor effect of both peptides is unclear. Direct action on tubular transport via renin and prorenin receptor has not yet been reported.

The renin-angiotensin system (RAS) affects both the innate and adaptive immune responses. Since hyperactive RAS has been associated with several diseases, the contribution of tissue RAS to the progression of immune and non-immune conditions has been considered in the recent years. It has a well-established role in fibrinogenesis, leukocyte infiltration, activity of T cells and has been shown to be chemotactic to macrophages, T cells, and natural killer cells. Nitric oxide (NO) is synthesized by many cell types involved in immunity and inflammation and plays an important role in hypotension and regulates the functional activity, growth and death of many immune and inflammatory cell types. Current evidences suggest that catecholamines (CAs) play a key role in activating and limiting inflammatory and immune reactions. In this chapter, we will discuss some aspects related to the role of these molecules in inflammatory process and immunologically mediated conditions.