Gut-Immune-Kidney Axis, Hypertension, and Renal End-Organ Damage
PROJECT SUMMARY/ABSTRACT Nearly half of the ~120 million Americans with hypertension are salt-sensitive and confer a higher risk of cardiovascular and kidney disease. Only 26% of hypertensive patients reach blood pressure (BP) control, indicating the urgent need to study novel mechanistic pathways in hypertension. The gut microbiota and immune system are critical in hypertension in males; this is largely unknown in females. This grant will address this knowledge gap by testing the role of the gut microbiota and its derived metabolites to modulate immune mechanisms known to contribute to salt-sensitive hypertension and renal end-organ damage. Mechanistic studies will be performed in male and female Dahl Salt-Sensitive (SS) rats, with translational studies performed in stored biological samples from humans consuming a diet high in salt. Dahl SS rats, a model consistent with human salt-sensitive hypertension, exhibit a greater degree of salt- sensitivity and associated renal end-organ damage in males compared to females. Through microbiota transfer studies, we know the gut microbiota plays a causal role in the regulation of BP and the extent of renal damage and renal T cell infiltration. We have observed stark sex differences in gut microbiota composition and gut- derived metabolites. It therefore begs the question of how sex-specific microbiota and its metabolites impact T cell function and ultimately, salt-sensitivity. This proposal, deemed meritorious for prior R56 support, will test the central hypothesis that the gut microbiota produces pathological metabolites in males (carnitine/TMAO) and protective metabolites in females (SCFAs), and these metabolites exert their actions on blood pressure and the kidney by altering T cell activation. Aim 1 will test whether sex differences in gut microbiota function alters the severity of salt-sensitive hypertension and renal damage. Sex-specific microbiota transfer and hormone manipulation studies (i.e. gonadectomy, Sry transgenic SS rat) will reveal whether the gut microbiota sex- and hormone-dependently contributes to salt- sensitivity in SS rats. Aim 2 will test whether the sex-specific influence of the gut microbiota on disease severity is mediated by gut-derived metabolites (increased TMAO in males versus increased SCFAs in females) and will determine the effect of these metabolites on T cell activation. Functional T cell changes in response to either sex-specific gut microbiota manipulation or gut metabolites will be assessed by measuring alterations to T cell gene expression, bioenergetics, and cytokine production. Parallel translational studies in urine, stool, serum, and PBMCs from humans consuming a diet high in salt will assess whether sex differences in microbiota, metabolites, and inflammation can explain sex differences in BP in humans. These studies will reveal key mechanisms related to gut-immune-kidney crosstalk and provide the preclinical and human basis for developing novel targets to improve BP control and kidney disease.
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Imported from NIH RePORTER | Grant 1R01HL187986-01.
Open sourceOverview
Grant agreement 1R01HL187986-01
Open sourcePROJECT SUMMARY/ABSTRACT Nearly half of the ~120 million Americans with hypertension are salt-sensitive and confer a higher risk of cardiovascular and kidney disease. Only 26% of hypertensive patients reach blood pressure (BP) control, indicating the urgent need to study novel mechanistic pathways in hypertension. The gut microbiota and immune system are critical in hypertension in males; this is largely unknown in females. This grant will address this knowledge gap by testing the role of the gut microbiota and its derived metabolites to modulate immune mechanisms known to contribute to salt-sensitive hypertension and renal end-organ damage. Mechanistic studies will be performed in male and female Dahl Salt-Sensitive (SS) rats, with translational studies performed in stored biological samples from humans consuming a diet high in salt. Dahl SS rats, a model consistent with human salt-sensitive hypertension, exhibit a greater degree of salt- sensitivity and associated renal end-organ damage in males compared to females. Through microbiota transfer studies, we know the gut microbiota plays a causal role in the regulation of BP and the extent of renal damage and renal T cell infiltration. We have observed stark sex differences in gut microbiota composition and gut- derived metabolites. It therefore begs the question of how sex-specific microbiota and its metabolites impact T cell function and ultimately, salt-sensitivity. This proposal, deemed meritorious for prior R56 support, will test the central hypothesis that the gut microbiota produces pathological metabolites in males (carnitine/TMAO) and protective metabolites in females (SCFAs), and these metabolites exert their actions on blood pressure and the kidney by altering T cell activation. Aim 1 will test whether sex differences in gut microbiota function alters the severity of salt-sensitive hypertension and renal damage. Sex-specific microbiota transfer and hormone manipulation studies (i.e. gonadectomy, Sry transgenic SS rat) will reveal whether the gut microbiota sex- and hormone-dependently contributes to salt- sensitivity in SS rats. Aim 2 will test whether the sex-specific influence of the gut microbiota on disease severity is mediated by gut-derived metabolites (increased TMAO in males versus increased SCFAs in females) and will determine the effect of these metabolites on T cell activation. Functional T cell changes in response to either sex-specific gut microbiota manipulation or gut metabolites will be assessed by measuring alterations to T cell gene expression, bioenergetics, and cytokine production. Parallel translational studies in urine, stool, serum, and PBMCs from humans consuming a diet high in salt will assess whether sex differences in microbiota, metabolites, and inflammation can explain sex differences in BP in humans. These studies will reveal key mechanisms related to gut-immune-kidney crosstalk and provide the preclinical and human basis for developing novel targets to improve BP control and kidney disease.