Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats

Zhai, Limin; Gu, Junfei; Yang, Di; Wen, Hao; Wang, W.; Ye, Shandong

doi:10.1111/1753-0407.12437

Cited by 36 publications

(24 citation statements)

References 24 publications

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“…Numerous in vitro and in vivo studies have indicated that metformin attenuates renal fibrogenesis, mainly by activating activity biomarkers of AMP‐activated protein kinase and target of rapamycin, thus exerting an antiapoptotic effect on podocytes in a high‐glucose environment and reducing the loss of podocytes in DM nephropathy . Diabetic rats, when treated with 150, 300, or 500 mg/kg of metformin for 8 weeks, had significant dose‐dependent reductions in urinary albumin, nephrin concentration, 8‐hydroxydeoxyguanosine level, glomerular basement membrane thickness, and foot process fusion rate compared with the control type 2 model rats …”

Section: Discussionmentioning

confidence: 99%

“…8,[22][23][24] Diabetic rats, when treated with 150, 300, or 500 mg/kg of metformin for 8 weeks, had significant dose-dependent reductions in urinary albumin, nephrin concentration, 8-hydroxydeoxyguanosine level, glomerular basement membrane thickness, and foot process fusion rate compared with the control type 2 model rats. 25,26 The potential renoprotective effect of metformin has been challenged. Hsu et al 10 reported that continual use of metformin was associated with a decline in the estimated glomerular filtration rate in patients with type 2 DM and moderate CKD.…”

Section: Discussionmentioning

confidence: 99%

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Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

Lee

Chang

et al. 2019

The Journal of Clinical Pharma

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Animal studies have demonstrated that metformin exerts a renoprotective effect. Human studies of patients with diabetes mellitus (DM) regarding the association of metformin use with end‐stage renal disease (ESRD) are lacking. Patients with type 2 DM and without a history of kidney disease who were enrolled under the pay‐for‐performance program of the National Health Insurance in Taiwan were identified. Those who received ≥90 cumulative defined daily doses of metformin within 1 year were selected (metformin users) and compared with a 1:1 propensity score–matched metformin nonuser cohort. Primary and secondary outcomes were development of ESRD and chronic kidney disease (CKD), respectively. Independent predictors were investigated using Cox regression analysis. A total of 24 158 pairs of metformin users and nonusers were enrolled, with an incidence of ESRD of 1908 and 1723 and CKD of 1095 and 1056 cases per 100 000 person‐years, respectively. Metformin use was independently associated with increased risks of ESRD (adjusted hazard ratio, 1.22; 95% confidence interval, 1.12‐1.32) and CKD (adjusted hazard ratio, 1.25; 95% confidence interval, 1.12‐1.40) in a dose‐response relationship. Patients with hypertension plus nonuse of angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers potentiated kidney damage by metformin. In patients with DM, use of metformin may increase the risk of ESRD and CKD. Health care professionals should be alert and closely monitor renal function when prescribing metformin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

Lee

Chang

et al. 2019

The Journal of Clinical Pharma

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“…Various mechanisms have been proposed. In rats with T2D, metformin increases the expression of nephrin and podocalyxin, both known to be downregulated or mislocalized in DKD . Treatment of primary rat podocytes with metformin activates protein deacetylase sirtuin 1 (SIRT1) and AMPK, and prevents high glucose‐induced downregulation of SIRT1 expression .…”

Section: Does Ship2 Convey the Renoprotective Effects Of Metformin?mentioning

confidence: 99%

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Lehtonen

2019

Acta Physiologica

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SHIP2 (Src homology 2 domain‐containing inositol 5′‐phosphatase 2) belongs to the family of 5′‐phosphatases. It regulates the phosphoinositide 3‐kinase (PI3K)‐mediated insulin signalling cascade by dephosphorylating the 5′‐position of PtdIns(3,4,5)P3 to generate PtdIns(3,4)P2, suppressing the activity of the pathway. SHIP2 mouse models and genetic studies in human propose that increased expression or activity of SHIP2 contributes to the pathogenesis of the metabolic syndrome, hypertension and type 2 diabetes. This has raised great interest to identify SHIP2 inhibitors that could be used to design new treatments for metabolic diseases. This review summarizes the central mechanisms associated with the development of diabetic kidney disease, including the role of insulin resistance, and then moves on to describe the function of SHIP2 as a regulator of metabolism in mouse models. Finally, the identification of SHIP2 inhibitors and their effects on metabolic processes in vitro and in vivo are outlined. One of the newly identified SHIP2 inhibitors is metformin, the first‐line medication prescribed to patients with type 2 diabetes, further boosting the attraction of SHIP2 as a treatment target to ameliorate metabolic disorders.

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“…Varios estudios han demostrado la existencia de daño renal en ratas con sobrecarga de fructosa (Gersch y col., 2007;Prince y col., 2016;Zhai y col., 2017). En este estudio, observamos la presencia de microalbuminuria y la reducción en la expresión de nefrina en las ratas del grupo F, en la semana 12 de tratamiento.…”

Section: Daño Renalunclassified

Effects of chronic fructose overload on renal dopaminergic system: alteration of urinary L-dopa/dopamine index correlates to hypertension and precedes kidney structural damage

Mikusic

Kouyoumdzian

Mauro

et al. 2018

The Journal of Nutritional Biochemistry

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Insulin resistance induced by a high-fructose diet has been associated to hypertension and renal damage. The aim of this work was to assess alterations in the urinary L-dopa/dopamine ratio over three time periods in rats with insulin resistance induced by fructose overload and its correlation with blood pressure levels and the presence of microalbuminuria and reduced nephrin expression as markers of renal structural damage. Male Sprague-Dawley rats were randomly divided into six groups: control (C) (C4, C8 and C12) with tap water to drink and fructose-overloaded (FO) rats (FO4, FO8 and FO12) with a fructose solution (10% w/v) to drink for 4, 8 and 12 weeks. A significant increase of the urinary L-dopa/dopamine ratio was found in FO rats since week 4, which positively correlated to the development of hypertension and preceded in time the onset of microalbuminuria and reduced nephrin expression observed on week 12 of treatment. The alteration of this ratio was associated to an impairment of the renal dopaminergic system, evidenced by a reduction in renal dopamine transporters and dopamine D1 receptor expression, leading to an overexpression and overactivation of the enzyme Na, K-ATPase with sodium retention. In conclusion, urinary L-dopa/dopamine ratio alteration in rats with fructose overload positively correlated to the development of hypertension and preceded in time the onset of renal structural damage. This is the first study to propose the use of the urinary L-dopa/dopamine index as marker of renal dysfunction that temporarily precedes kidney structural damage induced by fructose overload.

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Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats

Abstract: Metformin protects kidney podocytes in T2DM model rats by dose-dependently adjusting renal nephrin expression.

Cited by 36 publications

References 24 publications

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

Association of Metformin Use With End‐Stage Renal Disease in Patients With Type 2 Diabetes Mellitus: A Nationwide Cohort Study Under the Pay‐for‐Performance Program

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

Effects of chronic fructose overload on renal dopaminergic system: alteration of urinary L-dopa/dopamine index correlates to hypertension and precedes kidney structural damage

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