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TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)-treated Sprague-Dawley rats.

ABSTRACT: Canonical transient receptor potential-6 (TRPC6) channels have been implicated in the progression of several forms of kidney disease (1). While there is strong evidence that glomerular TRPC6 channels are dysregulated in diabetic nephropathy (DN), there is no consensus as to whether deletion or inactivation of TRPC6 is protective in animal models of DN. A previous study in Dahl salt-sensitive rats suggests that TRPC6 knockout has a modest protective effect in streptozotocin (STZ)-induced DN (2). In the present study, we examined whether inactivation of TRPC6 channels by CRISPR/Cas9 editing (Trpc6 del/del rats) affects progression of STZ-induced DN in Sprague-Dawley rats. Wild-type littermates (Trpc6 wt/wt rats) were used as controls. We observed that a single injection of STZ resulted in severe hyperglycemia that was sustained over a 10-week period, accompanied by a marked reduction in circulating C-peptide, dyslipidemia, and failure to gain weight compared to vehicle-treated animals. Those effects were equally severe in Trpc6 wt/wt and Trpc6 del/del rats. STZ treatment resulted in increased urine albumin excretion at 4, 8, and 10 weeks after injection, and this effect was equally severe in Trpc6 wt/wt and Trpc6 del/del rats. TRPC6 inactivation had no effect on blood urea nitrogen (BUN), plasma creatinine concentration, urine nephrin excretion, or kidney weight:body weight ratio measured 10 weeks after STZ injection. STZ treatment evoked modest and equivalent mesangial expansion in Trpc6 wt/wt and Trpc6 del/del rats. In summary, we observed no protective effect of TRPC6 inactivation on STZ-induced DN in rats on the Sprague-Dawley background.

SUBMITTER: Hassanzadeh Khayyat N

PROVIDER: S-EPMC6996301 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)-treated Sprague-Dawley rats.

Hassanzadeh Khayyat Naghmeh N Kim Eun Young EY Dryer Stuart E SE

FASEB bioAdvances 20191202 12

Canonical transient receptor potential-6 (TRPC6) channels have been implicated in the progression of several forms of kidney disease (1). While there is strong evidence that glomerular TRPC6 channels are dysregulated in diabetic nephropathy (DN), there is no consensus as to whether deletion or inactivation of TRPC6 is protective in animal models of DN. A previous study in Dahl salt-sensitive rats suggests that TRPC6 knockout has a modest protective effect in streptozotocin (STZ)-induced DN (2). ...[more]

PMID: 32123821

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Project description:Type 2 diabetes (T2D) adversely affects the normal functioning, intrinsic material properties, and structural integrity of many tissues, and bone fragility is one of them. To simulate human T2D and to investigate diabetic bone fragility, many rodent diabetic models have been developed. Still, an outbred genetically normal nonobese diabetic rat model is not available that can better simulate the disease characteristics of nonobese T2D patients, who have a high prevalence in Asia. In this study, we used a combination treatment of high-fat diet (4 weeks, 58% kcal as fat) and low-dose streptozotocin (STZ; 35 mg/kg i.p. at the end of the fourth week) to develop T2D in female Sprague-Dawley (SD) rats. After 8 weeks of the establishment of the T2D model, the femoral bones were excised after euthanizing rats (animal age approximately 21 to 22 weeks; n = 10 with T2D, n = 10 without diabetes). The bone microstructure (μCT), mechanical, and material properties (three-point bending, cyclic reference point indentation, nanoindentation), mean mineral crystallite size (XRD), bone composition (mineral-to-matrix ratio, nonenzymatic cross-link ratio [NE-xLR], Fourier transform-infrared microspectroscopy), and total fluorescent advanced glycation end products were analyzed. We found that diabetic bone had reduced whole-bone strength and compromised structural properties (μCT). The NE-xLRs were elevated in the T2D group, and strongly and negatively correlated with postyield displacement, which suggests bone fragility was caused by a lack of glycation control. Along with that, the decreased mineral-to-matrix ratio and modulus, increased indentation distance increase, and wider mineral crystallite size in the T2D group were evidence that the diabetic bone composition and material properties had changed, and bone became weaker with a tendency to easily fracture. Altogether, this model simulates the natural history and metabolic characteristics of late-stage T2D (insulin resistance and as disease progress develops, hypoinsulinemia) for nonobese young (and/or adolescent) T2D patients (Asians) and provides potential evidence of diabetic bone fragility at various organization levels. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)-treated Sprague-Dawley rats.

Publications

TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)-treated Sprague-Dawley rats.

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