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Theranostics, Published 2026-1-14; 16(8):3996-4018. | doi:10.7150/thno.124015 Hyperglycemia in combination with excess fat intake promotes renal pyroptosis and fibrosis through Gα12-dependent endoplasmic reticulum stress

Muhammad Sohaib Khan¹, Boram Kim¹, Yerim Jeon¹, Jihoon Tak^1,5, Yun Seok Kim⁶, Sang Gil Lee⁷, Eun Byul Lee⁷, Chang-hoon Lee⁴, Cheol Bin Eom¹³, Hyun Sook Lee⁸, Hyeon-Ki Jang^9,10, Nakyeom Lee^1,11, Jeong Hae Kie¹², Jee Myung Yang^8*, Yoon Mee Yang^13*, Sang Geon Kim^1,2,3*

¹College of Pharmacy, Dongguk University, Goyang-si, Kyeonggi-do 10326, Republic of Korea.
²Department of Medicine, Graduate School, Dongguk University, Goyang-si, Kyeonggi-do 10326, Republic of Korea.
³Dongguk University Medical Center, Goyang-si, Kyeonggi-do 10326, Republic of Korea.
⁴BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
⁵Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
⁶College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Korea.
⁷Center of Research and Development, A Pharma Inc, Goyang-si, Gyeonggi-do, Republic of Korea.
⁸Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, #88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Research and Development Institute, A Pharma Inc, Goyang-si, Gyeonggi-do, Republic of Korea.
⁹Kangwon National University, Chuncheon 24341, South Korea.
¹⁰Multidimensional Genomics Research Center, Kangwon University, Chuncheon 24341, South Korea.
¹¹Arlico Pharm, Central Lab, B-dong, #401~9, 338, Gwanggyojungang-ro, Suji-gu, Yongin-si, Gyeonggi-do, Korea.
¹²Department of Pathology, NHIS Ilsan Hospital, Goyang, Gyeonggi-do, 10444, Republic of Korea.
¹³School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, 06419, Republic of Korea.

^*Corresponding authors: Sang Geon Kim, Ph.D., Yoon Mee Yang, Ph.D., and Jee Myung Yang, M.D., Ph.D.

Abstract

Background: Chronic exposure to free fatty acids (FFAs) and glucose may disrupt metabolic homeostasis and initiate pathological processes. This study investigated the effects of hyperglycemia and fat overload on renal endoplasmic reticulum (ER) stress, pyroptosis and fibrogenesis in mice and the underlying basis. We hypothesized that the combined insult would more severely induce Gα12-dependent ER stress and renal complications.

Methods: Mice were subjected to either high fat diet (HFD)+streptozotocin (STZ), or STZ treatment, and AZ2 was used as an anti-diabetic agent. Blood sera were used for blood biochemistry, and tissues were employed for RNA sequencing, immunoblottings, TEM, histology and immunohistochemistry. HEK293 and other cells were used for high glucose (HG) and palmitate treatment, or Gα12 or siGα12 transfection.

Results: The combined HFD and STZ treatment, showing enrichment of genes related to GPCR signaling, inflammasome, ER stress, and pyroptosis in the RNA-sequencing analysis, upregulated Gα12 in the kidney, alongside increased PGC1α and PPARα. IRE1α and ATF6 were elevated without an increase in GRP78. This was accompanied by elevated blood glucose, creatinine, and BUN levels. We also found increases of pro-IL-1β, IL-1β, caspase-1, and NLRP3, demonstrating pyroptosis. Immunoassays revealed increased fibrosis markers. AZ2 reversed these changes. STZ treatment alone exhibited mild complications in the absence of Gα12 induction despite severe hyperglycemia. In cell-based assays, HG+palmitate elicited IRE1 activation along with Gα12 overexpression although HG alone had a minimal effect. Overexpression of Gα12 facilitated the effect of HG+palmitate on ER stress, pyroptosis, and fibrosis, whereas Gα12 knockdown had the opposite effect, as corroborated by the outcomes obtained using STZ-treated Gα12-/-, Gα12+/-, and Gα13 liver-specific KO mice.

Conclusion: These findings support the role of HG and lipid overload combination in driving renal pyroptosis and fibrogenesis through Gα12-mediated ER stress and inflammasome, delineating the mechanism underlying the conditions of diabetic renal complications and pharmacological intervention.

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