Regulation of renal function by the peroxisome proliferator-activated receptor-alpha: A novel target for treating hypertension

Abstract

Approximately 37 million people in the U.S. have chronic kidney disease, which is a major risk factor for cardiovascular and end stage renal diseases. We have identified a nuclear receptor, peroxisome proliferator-activated receptor – alpha (PPAR-α), that plays a major role in regulating renal glomerular filtration rate in an experimental model of hypertension. Targeting PPAR-α signaling provides novel therapeutic strategies for reducing hypertension associated chronic kidney disease. PPAR-α knockout (KO) mice exhibit increased renal inflammation and blood pressure response to Angiotensin II (Ang II). In this study, we investigated the role of PPAR-α in renal function in a mouse model of hypertension. Male 4-month-old wild type (WT) and PPAR-α KO mice were instrumented with radio transmitters by artery canulation (Data Science International). This method minimizes stress and artifacts by avoiding the use of tethering, restraining, or anesthetizing the mice during data sampling. After recovery from surgery, we continuously measured mean arterial pressure (MAP) via radio telemetry in conscious ambulatory mice. After baseline MAP was established, vehicle (Veh; saline) or Ang II were infused using an osmotic minipump at a slow pressor dose (400 ng/kg/min) for 12 days. On day 12, we injected an intravenous bolus of fluorescin-sinistrin (3.74 ml/g body weight) and collected 8 blood samples (20 μl/sample) during a 75-minute period to enable calculation of the glomerular filtration rate (GFR) using [GFR = I/(A/a + B/b]. Similar to our prior observations, no significant (ns) differences in baseline MAP were observed between WT and PPAR-α KO mice [(mmHg): WT (n=6), 111±20 vs. PPAR-α KO (n=6), 113 ± 10; ns] whereas after 12 days of the slow pressor effect of Ang II, MAP was increased in both strains [(mmHg): WT (n=8), 138 ± 11# vs. PPAR-α KO (n=8), 156 ± 16#; #p<0.05 vs. basal, same strain]; however, the increase in MAP was greater in the PPAR-α KO (43 mmHg) compared to WT (27 mmHg) mice. The absence of PPAR-α reduced GFR by 24% under basal conditions [(μl/min): WT (n=3), 346 ± 20 vs. PPAR-α KO (n=3), 275 ± 27*, *p<0.05 vs WT]. After 12 days of Ang II infusion, GFR was reduced in WT mice by 27% and did not further reduce GFR in PPAR-α KO mice [(μl/min): WT (n=6), 251 ± 11# vs. PPAR-α KO (n=6), 277 ± 61; #p<0.05 vs. basal, same strain]. PPAR-α protects mice from worsening hypertension and is critical to preserving GFR during normotensive conditions. Ongoing studies are further investigating how PPAR-α regulates renal function. These finding suggest therapeutics designed to increase PPAR-α activity could have clinical benefit in chronic kidney disease. Howard University Research Centers at Minority Institutions, Georgetown-Howard Universities Center for Clinical and Translational Science, Howard University Aging Grant, K01HL092593 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.