Sedaka Randee, Huang Jifeng, Yamaguchi Shinobu, Lovelady Caleb, Hsu Jung-Shan, Shinde Sejal, Kasztan Malgorzata, Crossman David K, Saigusa Takamitsu
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States.
Front Med (Lausanne). 2023 Jul 19;10:1173674. doi: 10.3389/fmed.2023.1173674. eCollection 2023.
Disease severity of autosomal dominant polycystic kidney disease (ADPKD) is influenced by diet. Dietary protein, a recognized cyst-accelerating factor, is catabolized into amino acids (AA) and delivered to the kidney leading to renal hypertrophy. Injury-induced hypertrophic signaling in ADPKD results in increased macrophage (MФ) activation and inflammation followed by cyst growth. We hypothesize that the cystogenesis-prompting effects of HP diet are caused by increased delivery of specific AA to the kidney, ultimately stimulating MФs to promote cyst progression.
mice with and without Cre (CAGG-ER) were given tamoxifen to induce global gene deletion (KO). KO mice were fed either a low (LP; 6%), normal (NP; 18%), or high (HP; 60%) protein diet for 1 week (early) or 6 weeks (chronic). Mice were then euthanized and tissues were used for histology, immunofluorescence and various biochemical assays. One week fed kidney tissue was cell sorted to isolate tubular epithelial cells for RNA sequencing.
Chronic dietary protein load in mice increased kidney weight, number of kidney infiltrating and resident MФs, chemokines, cytokines and cystic index compared to LP diet fed mice. Accelerated cyst growth induced by chronic HP were attenuated by liposomal clodronate-mediated MФ depletion. Early HP diet fed KO mice had larger cystic kidneys compared to NP or LP fed counterparts, but without increases in the number of kidney MФs, cytokines, or markers of tubular injury. RNA sequencing of tubular epithelial cells in HP compared to NP or LP diet group revealed increased expression of sodium-glutamine transporter , chloride channel , and gluconeogenesis marker , accompanied by increased excretion of urinary ammonia, a byproduct of glutamine. Early glutamine supplementation in KO mice lead to kidney hypertrophy.
Chronic dietary protein load-induced renal hypertrophy and accelerated cyst growth in KO mice is dependent on both infiltrating and resident MФ recruitment and subsequent inflammatory response. Early cyst expansion by HP diet, however, is relient on increased delivery of glutamine to kidney epithelial cells, driving downstream metabolic changes prior to inflammatory provocation.
常染色体显性多囊肾病（ADPKD）的疾病严重程度受饮食影响。膳食蛋白质是一种公认的促进囊肿生长的因素，它被分解为氨基酸（AA）并输送到肾脏，导致肾脏肥大。ADPKD中损伤诱导的肥大信号导致巨噬细胞（MФ）活化增加和炎症反应，随后囊肿生长。我们假设高蛋白饮食促进囊肿形成的作用是由于特定氨基酸向肾脏的输送增加，最终刺激MФ促进囊肿进展。
对有或没有Cre（CAGG-ER）的小鼠给予他莫昔芬以诱导整体基因缺失（KO）。KO小鼠分别喂食低蛋白（LP；6%）、正常蛋白（NP；18%）或高蛋白（HP；60%）饮食1周（早期）或6周（慢性）。然后对小鼠实施安乐死，并将组织用于组织学、免疫荧光和各种生化分析。对喂食1周的肾脏组织进行细胞分选，以分离肾小管上皮细胞用于RNA测序。
与喂食LP饮食的小鼠相比，小鼠长期摄入高蛋白饮食会增加肾脏重量、肾脏浸润和驻留MФ的数量、趋化因子、细胞因子和囊肿指数。脂质体氯膦酸盐介导的MФ耗竭减弱了慢性HP诱导的囊肿生长加速。与喂食NP或LP饮食的同窝小鼠相比，早期喂食HP饮食的KO小鼠的囊肿性肾脏更大，但肾脏MФ数量、细胞因子或肾小管损伤标志物没有增加。与NP或LP饮食组相比，HP饮食组肾小管上皮细胞的RNA测序显示，谷氨酰胺钠转运体、氯通道和糖异生标志物的表达增加，同时尿氨（谷氨酰胺的一种副产品）排泄增加。在KO小鼠中早期补充谷氨酰胺会导致肾脏肥大。
在KO小鼠中，长期膳食蛋白质负荷诱导的肾脏肥大和囊肿生长加速依赖于浸润和驻留MФ的募集以及随后的炎症反应。然而，HP饮食引起的早期囊肿扩张依赖于谷氨酰胺向肾上皮细胞的输送增加，在炎症激发之前驱动下游代谢变化。
