Decreased tubuloglomerular feedback (TGF) response in high-fat diet induced obesity

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Obesity is associated with increased renal and glomerular damage and hypertension, but the mechanisms are not clear. Normally, kidneys autoregulate to keep the glomerular capillary pressure (PGC), renal blood flow and glomerular filtration rate in a steady state. In obesity, the kidney loses its autoregulatory capacity, leading to higher PGC, renal blood flow and glomerular filtration rate. Together, these may lead to glomerular damage. PGC is controlled mainly by the afferent arteriole (Af-Art) resistance. Af-Art resistance in turn is regulated by an intrinsic renal feedback mechanism known as tubuloglomerular feedback (TGF). TGF causes Af-Art constriction in response to an increase in sodium chloride (NaCl) in the macula densa, via the Na-K-2Cl cotransporter NKCC2. We previously found that in the Zucker rat model of obesity, TGF was decreased and this was associated with higher blood pressure (BP) and proteinuria. However, it is not known whether obesity induced by a high fat diet in normal Sprague Dawley (SD) rats could also affect TGF. We hypothesized that TGF would be attenuated in obesity caused by 16 weeks of high fat fed (HFD) feeding (60% fat) in SD rats. SD rats fed normal-fat diet (12% fat, NFD) served as control. HFD fed rats exhibited higher body weight (HFD: 833.7±33.3 vs. NFD: 682.3±24.8 grams, p<0.05) and were hypertensive under Inactin anesthesia (mean BP HFD: 131.4±3.6 vs.115.8±3.8 mmHg, p<0.05). We performed in-vivo renal micropuncture of individual rat nephrons while measuring stop-flow pressure (PSF), an index of PGC PSF decreases with an increase in Af-Art resistance. TGF response was measured as a decrease in PSF induced by changing the rate of late proximal perfusion from 0 to 40nl/min. Maximal TGF response was significantly smaller in HFD fed rats compared to the NFD rats (HFD: 4.1±0.9 vs. NFD: 10.2±0.6 mmHg, p<0.05) indicating attenuation of TGF by HFD. Baseline PGC was higher in HFD rats compared to NFD rats (HFD: 41.6±0.8 vs. NFD: 38.7.2±0.5 mmHg, p<0.05). We conclude that TGF is attenuated in HFD fed obese SD rats and this may contribute to increased renal blood flow and GFR observed in obesity. Hypertension, combined with an attenuated TGF response and increased PGC may explain higher renal damage caused by obesity.



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