Gastrin, via activation of PPARα, protects the kidney against hypertensive injury

Abstract

Hypertensive nephropathy (HN) is a common cause of end-stage renal disease with renal fibrosis; chronic kidney disease is associated with elevated serum gastrin. However, the relationship between gastrin and renal fibrosis in HN is still unknown. We, now, report that mice with angiotensin II (Ang II)-induced HN had increased renal cholecystokinin receptor B (CCKBR) expression. Knockout of CCKBR in mice aggravated, while long-term subcutaneous infusion of gastrin ameliorated the renal injury and interstitial fibrosis in HN and unilateral ureteral obstruction (UUO). The protective effects of gastrin on renal fibrosis can be independent of its regulation of blood pressure, because in UUO, gastrin decreased renal fibrosis without affecting blood pressure. Gastrin treatment decreased Ang II-induced renal tubule cell apoptosis, reversed Ang II-mediated inhibition of macrophage efferocytosis, and reduced renal inflammation. A screening of the regulatory factors of efferocytosis showed involvement of peroxisome proliferator-activated receptor α (PPAR-α). Knockdown of PPAR-α by shRNA blocked the anti-fibrotic effect of gastrin in vitro in mouse renal proximal tubule cells and macrophages. Immunofluorescence microscopy, Western blotting, luciferase reporter, and Cut&tag-qPCR analyses showed that CCKBR may be a transcription factor of PPAR-α, because gastrin treatment induced CCKBR translocation from cytosol to nucleus, binding to the PPAR-α promoter region, and increasing PPAR-α gene transcription. In conclusion, gastrin protects against HN by normalizing blood pressure, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis. Gastrin-mediated CCKBR nuclear translocation may make it act as a transcription factor of PPAR-α, which is a novel signaling pathway. Gastrin may be a new potential drug for HN therapy.

Qingda Granule Attenuates Angiotensin II-Induced Renal Apoptosis and Activation of the p53 Pathway

“…As one of the characteristics of hypertensive renal injury, renal tubular epithelial cell (RTEC) apoptosis leads to the progression of renal tubulointerstitial fibrosis ( Docherty et al, 2006 ; Ning et al, 2011 ; Johnson and Dipietro, 2013 ; Schelling, 2016 ; Russa et al, 2017 ; Dan et al, 2018 ), contributing to the development of end-stage nephropathy. Consistent with a previous study ( Gu et al, 2021 ), the current study revealed that Ang II infusion significantly increased the percentage of cell apoptosis in renal tissues and cultured RTEC, which were attenuated after QDG treatment, suggesting the potential of QDG treatment for both antihypertension and attenuation of renal injury. However, the role of QDG treatment on renal inflammation, oxidative stress, and fibrosis should be further explored in future studies.…”

Intestinal Gastrin/CCKBR (Cholecystokinin B Receptor) Ameliorates Salt-Sensitive Hypertension by Inhibiting Intestinal Na + /H + Exchanger 3 Activity Through a PKC (Protein Kinase C)-Mediated NHERF1 and NHERF2 Pathway

“…There are beneficial effects of inhibition of intestinal NHE3 in addition to BP regulation and end-organ protection. 28 , 54 The long-term subcutaneous infusion of gastrin for 7 to 28 days protected against hypertensive nephropathy by normalizing BP, decreasing renal tubule cell apoptosis, and increasing macrophage efferocytosis 55 Gastrin treatment for 28 days also exerted a protective effect on myocardial infarction. 56 In our study, the high-salt diet-mediated increase in renal injury was mitigated by gastrin-SiO 2 microspheres treatment for 7 weeks.…”

Gastrin exerts a protective effect against myocardial infarction via promoting angiogenesis

“…No. G1276, Sigma-Aldrich) (Gu et al 2021 ; Rooman and Bouwens 2004 ), or/and the CCK 2 R inhibitor, CI988 (0.5 mg/Kg body weight/day, 100 μL in the pump, Cat. No.…”

“…A study has shown that gastrin stimulated islet-cell growth and insulin secretion, which is proposed as a potential drug therapy for diabetes mellitus (Rehfeld 2019 ). Besides, gastrin plays an essential role in maintaining normal blood pressure (Chen et al 2013 ) and protecting the kidney function against hypertensive injury (Gu et al 2021 ). Diabetes and hypertension are important causes of coronary atherosclerotic heart disease.…”