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Xiong X, Yu H, Li X, Li Y, Zeng R, Wang Y, Zhang C, Xiong Y, Fu W, He H, Yin S, Li J. Conditional Knockout Kdm2a Reveals Crucial Involvement in Development and Function of Kidney Collecting Ducts. Int J Mol Sci 2025; 26:1230. [PMID: 39940999 PMCID: PMC11818494 DOI: 10.3390/ijms26031230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/27/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Lysine-specific histone demethylase 2 (Kdm2a) is essential for histone modifications involved in development and associated diseases. Nevertheless, the specific functions of Kdm2a in renal development and pathology remain largely unexplored. This study aimed to elucidate the roles of Kdm2a in sustaining the biological functions of the kidney by generating mutant mice with Kdm2a deletion using the Aqp2-cre/Loxp system. Our findings showed that Kdm2a is widely expressed across various mouse tissues, with particularly high expression in the kidney's cortex and medulla, surpassing that in other tissues. Despite no observable effects on morphology or survival following the conditional knockout of Kdm2a, there was a significant reduction in body weight and bilateral kidney weight compared to controls, most pronounced at the 5-week-old stage (p < 0.05). Post Kdm2a deletion, kidney metabolic functions were impaired, evidenced by altered levels of creatinine, urea, total cholesterol, and low-density lipoprotein. Histological examination revealed that Kdm2a-null kidneys exhibited signs of dysfunction, characterized by macrophage infiltration, fibrosis, inflammatory cell infiltration, and mild thrombosis. Further studies revealed that the expression of chemokine- and pro-inflammatory cytokine-related genes Il-6, Il-8, Tnf-a, and Il-1β was significantly increased in the kidneys of Kdm2a cKO mice compared with controls (p < 0.05). Additionally, the expression of reabsorption-related genes (Aqp-3, Aqp-5, and Aqp-8) was markedly downregulated in Kdm2a-deficient kidneys compared with controls (p < 0.05). Collectively, these findings suggest that Kdm2a is crucial for maintaining kidney function and development, partly through the suppression of inflammation and regulation of gene expression. However, the underlying molecular mechanisms of Kdm2a in kidney development warrant further investigation.
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Affiliation(s)
- Xianrong Xiong
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Hailing Yu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Xupeng Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Yuan Li
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Ruilan Zeng
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Yufan Wang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Chunhai Zhang
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Yan Xiong
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Wei Fu
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Honghong He
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
| | - Shi Yin
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
| | - Jian Li
- Key Laboratory for Animal Science of National Ethnic Affairs Commission, Southwest Minzu University, Chengdu 610041, China
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Exploitation of Ministry of Education, Southwest Minzu University, Chengdu 610041, China
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Okumura K, Grace H, Sogawa H, Yamanaga S. Acute kidney injury and the compensation of kidney function after nephrectomy in living donation. World J Transplant 2022; 12:223-230. [PMID: 36159072 PMCID: PMC9453297 DOI: 10.5500/wjt.v12.i8.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/27/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) incidence is growing rapidly, and AKI is one of the predictors of inpatient mortality. After nephrectomy, all the patients have decreased kidney function with AKI and recover from AKI. However, the characteristic and behavior of AKI is different from usual AKI and compensatory kidney function has been well known in the postoperative setting, especially in living donors. In this review, we have focused on the compensation of kidney function after nephrectomy in living donors. We discuss factors that have been identified as being associated with kidney recovery in donors including age, sex, body mass index, remnant kidney volume, estimated glomerular filtration rate, and various comorbidities.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Holly Grace
- Department of Surgery, New York Medical College, Valhalla, NY 10595, United States
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto 861-8520, Japan
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Theil G, Weigand K, Fischer K, Bialek J, Fornara P. Organ-Specific Monitoring of Solitary Kidney after Living Donation by Using Markers of Glomerular Filtration Rate and Urinary Proteins. Urol Int 2021; 105:1061-1067. [PMID: 34175841 DOI: 10.1159/000515674] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/01/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Effective follow-up after living kidney donation is important for maintaining the renal function of the donor. We investigated whether the estimated glomerular filtration rate (eGFR) and urinary protein and enzyme levels can provide important information regarding the state of the remaining kidney after donor nephrectomy. METHODS Seventy-five living donations were included (prospective/retrospective) in the study. The following parameters were measured up to 1 year after donor nephrectomy: serum creatinine and cystatin C as markers of the GFR; the high-molecular-weight urinary proteins as markers of glomerular injury; and the low-molecular-weight urinary proteins and urinary enzymes as markers of tubular function. RESULTS One year after kidney donation, the creatinine and cystatin C values were 1.38-fold increased than their initial values, while the eGFR was 32% lower. At that time, 38% of donors had a moderate or high risk of CKD progression. The biochemical urinary glomerular and tubular kidney markers examined showed different behaviors. After a transient increase, the glomerular proteins normalized. Conversely, the detection of low-molecular-weight urinary proteins and enzymes reflected mild tubular damage at the end of the study period. CONCLUSIONS Our findings suggest that for the evaluation of mild tubular damage, low-molecular-weight marker proteins should be included in the urine diagnostic of a personalized living kidney donor follow-up.
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Affiliation(s)
- Gerit Theil
- Medical Faculty of Martin Luther University Halle-Wittenberg, University Clinic and Outpatient Clinic for Urology, Halle/Saale, Germany
| | - Karl Weigand
- Medical Faculty of Martin Luther University Halle-Wittenberg, University Clinic and Outpatient Clinic for Urology, Halle/Saale, Germany
| | - Kersten Fischer
- Medical Faculty of Martin Luther University Halle-Wittenberg, University Clinic and Outpatient Clinic for Urology, Halle/Saale, Germany
| | - Joanna Bialek
- Medical Faculty of Martin Luther University Halle-Wittenberg, University Clinic and Outpatient Clinic for Urology, Halle/Saale, Germany
| | - Paolo Fornara
- Medical Faculty of Martin Luther University Halle-Wittenberg, University Clinic and Outpatient Clinic for Urology, Halle/Saale, Germany
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Okumura K, Yamanaga S, Tanaka K, Kinoshita K, Kaba A, Fujii M, Ogata M, Hidaka Y, Toyoda M, Uekihara S, Miyata A, Inadome A, Yokomizo H. Prediction model of compensation for contralateral kidney after living-donor donation. BMC Nephrol 2019; 20:283. [PMID: 31349815 PMCID: PMC6660650 DOI: 10.1186/s12882-019-1464-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 07/12/2019] [Indexed: 12/18/2022] Open
Abstract
Background Compensation of contralateral kidney function after living-donor kidney donation is well known, and many predictive factors have been proposed. However, no prediction model has been proposed. This study was performed to establish a tool with which to estimate the degree of compensation of the contralateral kidney after living-donor kidney donation. Methods We retrospectively analyzed 133 living donors for renal transplantation in our institution. We defined a favorable compensation as a post-donation estimated glomerular filtration rate (eGFR) at 1 year (calculated by the Chronic Kidney Disease Epidemiology Collaboration equation) of > 60% of the pre-donation eGFR. We analyzed the living donors’ clinical characteristics and outcomes. Results The median (range) donor age was 59 (24–79) years, median (range) body mass index was 22.9 (16.8–32.7) kg/m2, and median (range) body surface area was 1.6 (1.3–2.0) m2. All donors were Japanese, and 73% of the donors were biologically related. The median (range) donor pre-donation eGFR was 108.7 (82–144) ml/min/1.73 m2, and the median (range) post-donation eGFR at 1 year was 86.9 (43–143) ml/min/1.73 m2. Eighty-six percent of donors had compensatory hypertrophy. In the univariate analysis, age, female sex, history of hypertension, body surface area, and pre-donation eGFR were significantly associated with hypertrophy (p < 0.05). In the multivariate analysis, age, female sex, history of hypertension, and ratio of the remnant kidney volume to body weight were significantly associated with hypertrophy (p < 0.05). Based on these results, we created a compensation prediction score (CPS). The median (range) CPS was 8.7 (1.1–17.4). Receiver operating characteristic analysis showed strong diagnostic accuracy for predicting favorable compensation (area under the curve, 0.958; 95% confidence interval, 0.925–0.991, p < 0.001). The optimal cut-off value of the CPS was 5.0 (sensitivity, 92.0%; specificity, 89.5%). The CPS had a strong positive correlation with the post-donation eGFR (R = 0.797, p < 0.001). Conclusion The CPS might be useful tool with which to predict a favorable compensation of the contralateral kidney and remnant kidney function. If the CPS is low, careful management and follow-up might be necessary. Further investigations are needed to validate these findings in larger populations.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan.
| | - Kosuke Tanaka
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
| | - Kohei Kinoshita
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
| | - Akari Kaba
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
| | - Mika Fujii
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Masatomo Ogata
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Yuji Hidaka
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
| | - Mariko Toyoda
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Soichi Uekihara
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Akira Miyata
- Department of Nephrology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Akito Inadome
- Department of Urology, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan
| | - Hiroshi Yokomizo
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, 2-1-1 Nagamine-minami, Higashi-ku, Kumamoto, 861-8520, Japan
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