Global Deletion of DPP4 Prevents the Development of Salt-sensitive Hypertension in Obese Mice via Regulation of Sodium and Water Excretion

Abstract

Salt-sensitivity of hypertension (HTN) occurs in up to 50% of hypertensive patients and is more common in the older population, Blacks and the obesity/diabetes/hypertension subsets. The renin-angiotensin aldosterone system (RAAS), in particular Angiotensin II (Ang II) and aldosterone known to regulate the Na+/H+ exchanger isoform 3 (NHE3) and ENaC respectively, is thought to be activated in the obesity/diabetes/hypertension subsets and thereby plays an important role in salt-sensitive HTN. RAAS blockade is an acceptable treatment for salt-sensitive HTN along with the use of diuretics. However, not every patient can tolerate RAAS blockade. Recently, dipeptidyl peptidase 4 (DPP4) has been shown to bind to NHE3, colocalizes to the microvillar fractions with active NHE3 and DPP4 inhibition reduces sodium uptake into proximal tubule cells and isolated rat proximal tubules. In addition, DPP4 may act on more distal transporters. Furthermore, data from our lab has revealed that DPP4 knockout (DPP4KO) mice have a lower sodium balance both under conditions of high salt (1.23%) and low salt (0.02%) ingestion suggesting that DPP4 regulates sodium transport and/or balance under physiological conditions. However, whether DPP4 has any effects on salt-sensitive HTN and the underlying mechanisms remain unknown. Therefore, we hypothesized that the absence of DPP4 could mitigate the development of salt-sensitive HTN in an obesity model, by improving the natriuretic and diuretic response mediated by NHE3 and/or distal mechanisms. To this end, 6-8wk old DPP4KO and C57Bl/6 littermate wild-type (WT) mice were fed a control (CD) or Western diet (WD, high in refined fats and sugars) to induce obesity. Circulating (175%) and kidney (125%) DPP4 activity were both elevated in the obese WT mice compared to the CD-fed WT mice (100%) and DPP4KO mice had minimal DPP4 activity as expected. The lack of DPP4 prevented the increase in systolic blood pressure (~15 mmHg) in the obese animals, and the absence of the development of cardiac hypertrophy in this group corroborated the pressure effect. The development of salt-sensitive HTN in the obese WT mice was associated with a lower natriuretic and diuretic response assessed by the salt overload experiment, suggesting higher tubular reabsorption of sodium and water by the nephrons. In turn, the lack of DPP4 prevented the lowering of natriuretic and diuretic response in obese mice, indicating that the beneficial effect of the absence of DPP4 on the development of salt-sensitive HTN is closely related to effects on renal tubule transport. Importantly, a high salt diet increased sodium balance and blood pressure in the obese WT mice and DPP4 deletion mitigated this increase. Furthermore, on low salt diet, the absence of DPP4 led to “salt wasting” in the obese mice similar to the CD-fed mice. Surprisingly, gene and protein expression measurements showed involvement of distal tubule sodium transporters and aquaporins and not NHE3. In contrast, assessment of the DPP4 interactome in obese mice showed binding to Myosin 6 and APN, which may regulate proximal tubule transporters and hypertension. Transdermal measurements showed no changes in the glomerular filtration rate. In conclusion, deletion of DPP4 protects against the development of salt-sensitive hypertension in obese mice by improving the natriuretic and diuretic response likely via regulation of sodium and water transporters. FAPESP, Brazil NIH K08DK115886, USA. This is the full abstract presented at the American Physiology Summit 2024 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.