Salt-sensitive increase in macrophages in the kidneys of Dahl SS rats

Abstract

Studies of Dahl salt-sensitive (SS) rats have shown that renal CD3+ T cells and ED-1+ macrophages are involved in the development of salt-sensitive hypertension and renal damage. The present study demonstrated that the increase in renal immune cells, which accompanies renal hypertrophy and albuminuria in high-salt diet-fed Dahl SS rats, is absent in Sprague-Dawley and SSBN13 rats that are protected from the SS disease phenotype. Flow cytometric analysis demonstrated that >70% of the immune cells in the SS kidney are M1 macrophages. PCR profiling of renal myeloid cells showed a salt-induced upregulation in 9 of 84 genes related to Toll-like receptor signaling, with notable upregulation of the Toll-like receptor 4/CD14/MD2 complex. Because of the prominent increase in macrophages in the SS kidney, we used liposome-encapsulated clodronate (Clod) to deplete macrophages and assess their contribution to salt-sensitive hypertension and renal damage. Dahl SS animals were administered either Clod-containing liposomes (Clod-Lipo), Clod, or PBS-containing liposomes as a vehicle control. Clod-Lipo treatment depleted circulating and splenic macrophages by ∼50%; however, contrary to our hypothesis, Clod-Lipo-treated animals developed an exacerbated salt-sensitive response with respect to blood pressure and albuminuria, which was accompanied by increased renal T and B cells. Interestingly, those treated with Clod also demonstrated an exacerbated phenotype, but it was less severe than Clod-Lipo-treated animals and independent of changes to the number of renal immune cells. Here, we have shown that renal macrophages in Dahl SS animals sustain a M1 proinflammatory phenotype in response to increased dietary salt and highlighted potential adverse effects of Clod-Lipo macrophage depletion.

Selective Phosphodiesterase 1 Inhibitor BTTQ Reduces Blood Pressure in Spontaneously Hypertensive and Dahl Salt Sensitive Rats: Role of Peripheral Vasodilation

“…While SHR rats share important mechanistic features with Angiotensin II infusion model, it is, arguably, more representative of human disease (Doggrell and Brown, 1998). Another animal model used in the current investigation, Dahl salt-sensitive hypertension, capitalizes on different mechanisms of blood pressure regulation (Rapp, 1982) and commonly used to study salt-induced hypertension (Palygin et al, 2017;Fehrenbach et al, 2019;Lerman et al, 2019). Our current data obtained using a structurally unrelated compound further supports the critical involvement of PDE1 into the regulation of blood pressure via demonstration of therapeutic benefits in two independent rodent models of hypertension.…”

“…While SHR rats share important mechanistic features with Angiotensin II infusion model, it is, arguably, more representative of human disease (Doggrell and Brown, 1998). Another animal model used in the current investigation, Dahl salt-sensitive hypertension, capitalizes on different mechanisms of blood pressure regulation (Rapp, 1982) and commonly used to study salt-induced hypertension (Palygin et al, 2017;Fehrenbach et al, 2019;Lerman et al, 2019). Several studies have shown expression of PDE1 in the vascular wall (e.g., aorta, femoral, and mesenteric artery) of different rat strains, e.g., Wistar (Khammy et al, 2017;Laursen et al, 2017), Sprague Dawley (Giachini et al, 2011), and SHR rats (McMahon et al, 1989;Pontes et al, 2012).…”

Emerging Role of the Inflammasome and Pyroptosis in Hypertension

“…It is now widely acknowledged that low-grade or persistent inflammation is a key player in the development and maintenance of hypertension. Exhaustive research demonstrates the infiltration of immune cells, like T cells, macrophages, and dendritic cells in the kidneys, perivascular fat, or heart during the development and progression of hypertension [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. In particular, immune cell transfer studies performed by Guzik et al [ 15 ] demonstrated that the development of angiotensin II-induced and DOCA salt-induced hypertension was dependent on the presence of T cells.…”

The effect of macrophage-targeted interventions on blood pressure – a systematic review and meta-analysis of preclinical studies

“…Study characteristics. Details on study characteristics can be found in Table 1 (part I) [12][13][14][15]20,[24][25][26][27][28][29][30][31][32][33][34][35] and Supplemental Table 3 (part II). 13,14,[18][19][20][21]33,[36][37][38][39][40] Of the 18 macrophage depletion studies (part I), 9 studies involved rat models, 8 involved mouse models, and one study involved both.…”