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Linking Toll‐like Receptor 4, Gut Microbiota, and Doxycycline in the Hypertensive Kidney

Hypertension is one of the leading causes of chronic kidney disease (CKD) and affects approximately one‐third of the United States population. Toll‐like receptor 4 (TLR4) plays a role in the innate immune system through induction of NF‐κB‐mediated inflammatory response, which if unresolved, can lead to tissue damage. Activation of TLR4 is through recognition of foreign antigens, such as lipopolysaccharide (LPS), which is a product of gram‐negative bacteria. Several recent studies have revealed the gut microbiome can influence multiple physiological processes, such as metabolism, immunity, and blood pressure (BP) regulation. Doxycycline is routinely prescribed for a variety of illnesses and infections, however, the exact effects on gut microbiome composition and blood pressure regulation and kidney function have not been evaluated. In this study, we sought to determine the link between TLR4, gut microbiota and the kidney during hypertension and whether the broad‐spectrum antibiotic doxycycline could reverse the effects to mitigate renal dysfunction. C3H/HeJ (TLR4 deficiency) and C3H/HeOuJ (normal TLR4) mice were treated without or with Ang‐II (1000ng/kg−1/min−1) via mini osmotic pump for 4 weeks. Initial results indicated a blunted response in TLR4 deficient mice treated with Ang‐II as observed by a lower mean blood pressure compared to mice with functional TLR4. In addition, kidney injury marker (KIM‐1) and lactate dehydrogenase (LDH) were reduced in the tubules and glomeruli of the kidney, respectively, in TLR4‐deficient mice. Moreover, TLR4‐deficient mice were protected from inflammation‐mediated damage as evidenced by a decrease in IL‐6 and IL‐1β expression. Kidney function of mice lacking TLR4 treated with Ang‐II was improved as observed by a higher glomerular filtration rate and a lower resistive index of cortex and renal artery compared to controls. Hypertensive mice with normal TLR4 function were also found to have a decrease in plasma hydrogen sulfide (H2S) levels as well as hypermethylation of the H2S converting enzyme 3‐mercaptopyruvate sulfurtransferase compared to deficient TLR4 mice. Expression of zonulin, claudin 1, and occluding, tight‐junction proteins involved in the maintenance and integrity of the gut‐epithelial barrier, were found to be similar in Ang‐II TLR4‐deficient mice compared to untreated mice. In contrast, normal TLR4 mice showed lack of tight junction protein expression, indicating a compromised gut‐epithelial barrier. This result was supported by increased levels of plasma FITC‐dextran that was administered to mice at the end of the treatment period to assess gut leakage, as well as an increase in 16S bacterial expression in the kidney. In conclusion, our data suggests TLR4‐deficient mice have improved renal function and an intact gut‐epithelial barrier as well as normalized H2S levels. Current efforts are aimed at profiling the microbiome of these mice as well as assess the effects of doxycycline on gut microbiota composition and whether this antibiotic affects blood pressure regulation.