Abstract
Prenatal exposure to an inflammatory stimulus has been shown to cause renal damage in offspring. Our present study explored the role of intra-renal NF-κB activation in the development of progressive renal fibrosis in offspring that underwent prenatal exposure to an inflammatory stimulus. Time-dated pregnant rats were treated with saline (control group) or 0.79 mg/kg lipopolysaccharide (LPS) through intra-peritoneal injection on gestational day 8, 10 and 12. At the age of 7 weeks, offspring from control or LPS group were treated with either tap water (Con+Ve or LPS+Ve group) or pyrollidine dithiocarbamate (PDTC, 120mg/L), a NF-κB inhibitor, via drinking water starting (Con+PDTC or LPS+PDTC group), respectively, till the age of 20 or 68 weeks. The gross structure of kidney was assessed by hematoxylin-eosin, periodic acid–Schiff staining and Sirius red staining. The expression levels of TNF-α, IL-6, α-smooth muscle actin (α-SMA) and renin-angiotensin system (RAS) genes were determined by real time polymerase chain reaction and/or immunohistochemical staining. Our data showed that post-natal persistent PDTC administration efficiently repressed intra-renal NF-κB activation, TNF-α and IL-6 expression. Post-natal PDTC also prevented intra-renal glycogen deposition and collagenous fiber generation as evident by the reduced expression of collagen III and interstitial α-SMA in offspring of prenatal LPS exposure. Furthermore, post-natal PDTC administration reversed the intra-renal renin-angiotensin system (RAS) over-activity in offspring of prenatal LPS exposure. In conclusion, prenatal inflammatory exposure results in offspring’s intra-renal NF-κB activation along with inflammation which cross-talked with excessive RAS activation that caused exacerbation of renal fibrosis and dysfunction in the offspring. Thus, early life prevention of NF-κB activation may be a potential preventive strategy for chronic renal inflammation and progressive renal damage.
Highlights
The incidence and morbidity rates of cardiovascular disease (CVD) such as hypertension continue to rise despite ongoing research efforts in regard to primary and secondary prevention [1]
The protein levels of pp65 and total p65 were significantly increased in renal tissue of offspring that received prenatal exposure to LPS (Fig 1A), which indicates that intra-renal NF-κB was activated in adult offspring of prenatal exposure to LPS
We found that prenatal LPS exposure significantly increased the mRNA expression of TNF-α and IL-6 in renal tissue of offspring at the age of 20 weeks, whereas postnatal pyrollidine dithiocarbamate (PDTC) administration significantly reduced the mRNA expression of TNF-α and IL-6 (Fig 1B and 1C)
Summary
The incidence and morbidity rates of cardiovascular disease (CVD) such as hypertension continue to rise despite ongoing research efforts in regard to primary and secondary prevention [1]. A recent epidemiological study had demonstrated that the population involved with the prenatal exposure to the 1918 influenza pandemic showed ~ 20% excess cardiovascular disease [4]. These findings provide supportive evidence that prenatal inflammation is epidemiologically relevant to CVD. We previously found that prenatal exposure to inflammatory stimuli, such as lipopolysaccharides (LPS), the main component of gramnegative bacteria cellular wall [5], resulted in the development of hypertension in SpragueDawley (SD) rats [6]. As prenatal inflammatory exposure, such as infection [8], hepatitis [9] as well as arthritis [10], is still the most common public health problems during pregnancy, further research is required in this area to uncover the mechanisms of prenatal programmed hypertension and other CVD complications
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